Deciphering the modulatory role of short-chain fatty acids in Parkinson’s disease via phosphorylation-dependent signaling mechanisms

Metabolic pathway of SCFAs

SCFAs, saturated fatty acids with fewer than six carbon atoms, are primarily derived from the anaerobic fermentation of indigestible carbohydrates by gut microbiota, including Bacteroides and Prevotella, with these fatty acids being predominantly released in the gut and reaching their highest concentrations in the colon (Li et al., 2022; Hays, Pfaffinger & Ryznar, 2024). Studies employing gas chromatography (GC) and high-performance liquid chromatography (HPLC), which are considered the gold standards for quantifying SCFAs, have demonstrated that SCFAs are most concentrated in the proximal colon, with concentrations ranging from 70 to 140 mmol/L. The primary SCFAs include acetate (C2), propionate (C3), and butyrate (C4), which occur in an approximate ratio of 60:25:15 (Cummings et al., 1987; Meesters et al., 2007; Hays, Pfaffinger & Ryznar, 2024). Approximately 90% of SCFAs are rapidly absorbed by intestinal cells due to their high volatility and water solubility (Roediger, 1980). A small fraction of SCFAs in neutral form crosses the intestinal epithelial barrier via passive diffusion, whereas the majority, in their ionized state, are actively transported into colonic cells through epithelial membrane receptors, including H⁺-dependent monocarboxylate transporter-1 (MCT1, SLC16A1), Na⁺-coupled monocarboxylate transporter-1 (SMCT1, SLC5A8), and the basolateral transporters MCT4 (SLC16A3) and MCT5 (SLC16A4) (Gill et al., 2005; Kaji et al., 2015; Stumpff, 2018). Inside the cells, SCFAs, particularly butyrate, undergo β-oxidation and the tricarboxylic acid cycle to supply 60–70% of the energy required by colonic cells and contribute approximately 10% of the energy needed for daily human physiological demands (Guo et al., 2023b). Following absorption, SCFAs enter systemic circulation via the hepatic portal vein. However, due to the first-pass metabolism in the liver, the concentration of acetate in systemic circulation is only 100–200 μM, while propionate and butyrate levels are even lower, at 1–15 μM (Moreau et al., 2003; Meesters et al., 2007). SCFAs bypassing the liver can cross the blood-brain barrier (BBB) to reach the brain, where the average concentrations of propionate and butyrate are 18.8 and 17.0 pmol/mg, respectively (Silva, Bernardi & Frozza, 2020). Notably, the concentrations of SCFAs used in in vitro experiments often exceed the physiological levels found in the human brain. This discrepancy represents an important limitation when interpreting experimental findings, as supraphysiological exposure to SCFAs may elicit effects and activate signaling pathways that are unlikely to be engaged at brain-relevant concentrations in vivo.

SCFAs signaling pathways

Extensive research has identified two primary mechanisms by which SCFAs influence biological functions in the human body. First, SCFAs interact with GPCRs, primarily GPR41, GPR43, and GPR109A, which play critical roles in regulating host immune and metabolic responses (Fig. 1) (Du et al., 2024). Second, SCFAs directly inhibit HDAC activity, which enables precise chromatin remodeling and regulation of gene expression. This mechanism profoundly influences gene expression across various cell types, enhancing their adaptability to environmental changes (Du et al., 2024). In the context of Parkinson’s disease, these two signaling modes provide a mechanistic framework for interpreting experimental and clinical data on gut microbiota–derived SCFAs. Using an α-synuclein–overexpressing mouse model, Sampson et al. (2016) demonstrated that gut microbiota and their SCFA metabolites are necessary to elicit PD-like motor deficits and neuroinflammation: germ-free or antibiotic-treated mice show reduced α-synuclein aggregation and microglial activation, whereas recolonization with complex microbiota or oral SCFA supplementation reinstates these pathological and behavioral phenotypes. Together with human studies reporting altered SCFA profiles, impaired gut barrier integrity and dysregulated free fatty acid receptor expression in PD (Unger et al., 2016; Aho et al., 2021; Chen et al., 2022; Liao et al., 2024), these findings support the view that GPCR- and HDAC-mediated SCFA signaling constitutes a key molecular interface along the gut–brain axis, which will be further elaborated in the following sections.

Abnormal aggregation of α-synuclein

α-synuclein, a 140-amino-acid soluble monomeric protein, predominantly localizes to synaptic terminals, where it facilitates vesicle transport and neurotransmitter release (Schweighauser et al., 2020). During the pathological progression of PD, mutations in the SNCA gene and stress conditions drive α-synuclein to shift from a soluble α-helix to an insoluble β-sheet conformation, forming oligomers (Mehra, Sahay & Maji, 2019). Growing evidence suggests that early-stage oligomers are the primary neurotoxic agents, impairing synaptic function, damaging organelles such as mitochondria and lysosomes, and ultimately causing neuronal dysfunction and death, with early synaptic dysfunction being a critical step in PD pathogenesis, while these oligomers also exert direct toxicity and promote the aggregation of normal α-synuclein, leading to insoluble fibrillar deposits that eventually form classic Lewy bodies (Braak et al., 2003a; Alam et al., 2019). Abnormal α-synuclein aggregation induces neuronal dysfunction, mitochondrial impairment, and inflammatory responses, while promoting its pathological spread through inter-neuronal transmission (Lehtonen et al., 2019). Early studies found that PD patients receiving fetal neuron transplants to restore DA neurons developed Lewy bodies in the transplanted neurons, raising significant concerns (Kordower et al., 2008; Li et al., 2008). Subsequent studies using α-synuclein-overexpressing animal models demonstrated its prion-like behavior, spreading pathologically between neurons and causing further cellular damage (Luk et al., 2012; Recasens et al., 2018; Tarutani & Hasegawa, 2019). This mechanism of “intercellular propagation” supports Braak et al.’s (2003a) staging theory, highlighting the spatial and temporal progression of PD pathology, and offers a molecular explanation for the early emergence of non-motor symptoms in PD. The formation of α-synuclein aggregates represents a pivotal event in PD pathology. However, the role of Ser129 phosphorylation (Ser129P) in this process remains unclear. Ser129 phosphorylation is extensively observed in α-synuclein within Lewy bodies and Lewy neurites in the brains of patients with PD, suggesting a strong association with aggregate formation (Anderson et al., 2006). If Ser129P directly drives pathological α-synuclein aggregation, its elevated levels should enhance neurodegeneration and cell death; however, animal studies do not support this hypothesis, as although S129D mutants exhibited slightly accelerated degeneration in models such as Drosophila and yeast, the overall data did not indicate significant neurodegenerative changes (Chen & Feany, 2005; Gitler et al., 2007; Soper et al., 2008). Traditional perspectives often overlook the physiological roles of Ser129P, viewing it solely as a pathological marker, while recent research suggests that Ser129P acts as a dynamic regulator with potential protective effects in early disease stages, modulating α-synuclein’s synaptic localization and interactions with other synaptic proteins to inhibit synaptic transmission, regulate neurotransmitter release, and maintain neuronal activity and synaptic function (Parra-Rivas et al., 2023). Furthermore, Ser129 phosphorylation may influence the aggregation process by stabilizing α-synuclein oligomers, potentially promoting the transition from oligomeric to fibrillar forms under pathological conditions (Parra-Rivas et al., 2023). Therefore, Ser129P should not be viewed merely as a direct pathological inducer. Investigating how Ser129P regulates α-synuclein through neuronal activity and protein-protein interactions may provide insights into the pathogenesis of PD and other synucleinopathies, paving the way for future therapeutic strategies.

Mitochondrial dysfunction and oxidative stress

Mitochondrial dysfunction represents a key pathological mechanism in the early stages of PD. It is closely associated with synaptic damage, overproduction of reactive oxygen species (ROS), disruption of calcium homeostasis, imbalance of neuronal microtubule acetylation and decreased intracellular adenosine triphosphate (ATP) synthesis (Nicoletti et al., 2021; Naren et al., 2023b). In PD models induced by chemical agents like MPTP and rotenone, these compounds impair mitochondrial complex I activity to exert their toxic effects. These models demonstrate a direct link between mitochondrial dysfunction and PD neuropathology, offering vital experimental insights into the disease mechanisms (Mani et al., 2021). Extensive research reveals that mitochondrial dysfunction in PD extends beyond impaired electron transport chain (ETC) activity. It also encompasses severe disruptions in mitochondrial structure and dynamics. Damage to mitochondrial architecture decreases ATP production, impairs neuronal energy metabolism, and accelerates neurodegeneration (Nicoletti et al., 2021; Naren et al., 2023a; Tryphena et al., 2023). During PD progression, the abnormal aggregation of α-synuclein induces the translocation of dynamin-related protein 1 (Drp1), a key regulator of mitochondrial fission, disrupting mitochondrial structure and impairing the dynamic fusion-fission balance essential for maintaining mitochondrial function (Krzystek et al., 2021). Mitophagy, the selective removal of damaged mitochondria, is essential for maintaining mitochondrial health and minimizing energy inefficiency, with PINK1 and the E3 ubiquitin ligase Parkin serving as key regulators; under excessive stress, mitochondria in PD lose membrane potential, leading to PINK1 accumulation on their outer membranes and subsequent ubiquitin phosphorylation, which recruits and activates Parkin through PINK1 phosphorylation, ultimately resulting in the ubiquitination and degradation of mitochondrial surface proteins (Narendra & Youle, 2024). However, α-synuclein aggregates severely impair Parkin function, and under α-synuclein influence, Parkin levels decline significantly, exacerbating mitochondrial toxicity (Sharma et al., 2024). Extensive genetic studies emphasize the critical role of mitochondria in PD pathology, with genes such as PRKN, PINK1, and LRRK2 implicated in mitochondrial bioenergetics disruption and quality control impairment; for instance, PINK1 and PRKN are essential for mitophagy regulation, while mutations in LRRK2, particularly the Gly2019Ser mutation, are strongly associated with PD, interfering with mitotic processes and mitochondrial dynamics, ultimately leading to extensive structural and functional mitochondrial collapse (Singh & Ganley, 2021). These findings clearly demonstrate the direct effects of genetic mutations on mitochondrial function, emphasizing the intricate and crucial role of genetic factors in PD pathology.

In various animal models of PD, the accumulation of ROS, including superoxide, hydrogen peroxide, and hydroxyl radicals, is frequently observed, providing strong evidence for the pivotal role of oxidative stress in neuronal degeneration (Ding et al., 2018). At moderate levels, ROS regulate cellular signaling and support normal physiological functions, but excessive ROS accumulation damages essential cellular components such as lipids, proteins, and DNA, leading to oxidative damage and triggering a cascade of pathological reactions (Umeno, Biju & Yoshida, 2017). DA neurons in the substantia nigra of PD patients are highly susceptible to oxidative stress due to their unique morphology and high energy requirements, with oxidative stress directly endangering these neurons and disrupting their complex network connections, and this susceptibility stemming from an imbalance between pro-oxidant and antioxidant systems, a key factor in PD progression (Ren et al., 2017). Consequently, oxidative stress is considered a major contributor to neuronal degeneration in PD pathology. This phenomenon is closely associated with mitochondrial dysfunction. Mitochondrial damage and ETC disruption—especially complex I (NADH dehydrogenase) inhibition—are primary sources of intracellular ROS overproduction in PD (Malpartida et al., 2021). Reduced electron transport efficiency causes ROS accumulation, which directly damages mitochondrial DNA (mtDNA) within mitochondria. mtDNA damage further impairs mitochondrial function, especially ETC activity, perpetuating a vicious cycle of “oxidative stress and mitochondrial dysfunction” (Picca et al., 2020).

Inflammation and immune response

Since the 1980s, the discovery of microglial activation and elevated pro-inflammatory cytokines in post-mortem PD brains has established neuroinflammation as a crucial component of PD pathology. The role of microglia in PD has been well-documented and extensively validated (Morris et al., 2024). As the primary innate immune cells of the CNS, activated microglia release significant amounts of pro-inflammatory cytokines and chemokines, including TNF-α, IL-6, and IL-8, with persistent microglial activation during disease progression serving as a source of inflammatory responses and directly contributing to the damage of DA neurons (Zhang, Tang & Illes, 2024). The hallmark pathological protein in PD, α-synuclein, is closely associated with neuroinflammation, and its interaction with CNTFR-α on DA neurons activates the JAK-STAT3 signaling pathway, further amplifying inflammation and microglial activation, thereby creating a self-perpetuating vicious cycle (Liu et al., 2010). Additionally, the abnormal aggregation of α-synuclein not only leads to neuronal damage but also serves as a key trigger for immune system activation, as α-synuclein directly interacts with toll-like receptors on microglia and astrocytes, initiating the downstream activation of the NLRP3 inflammasome and various inflammatory mediators, ultimately resulting in caspase-1-dependent mitochondrial damage and subsequent DA neuronal injury (Soraci et al., 2023; Brash-Arias et al., 2024). Notably, the NLRP3 inflammasome serves as a critical bridge between mitochondrial dysfunction and neuroinflammation, playing a pivotal role in this pathological interplay (Khot et al., 2022). Mitochondrial dysfunction in PD patients is associated with abnormal calcium (Ca²⁺) accumulation, impaired mitogen-activated protein kinase (MAPK) activity, and mitochondrial antiviral signaling protein (MAVS) alterations, which collectively overactivate the NLRP3 inflammasome, promoting the release of pro-inflammatory cytokines such as IL-1β and IL-18 and thereby exacerbating neuroinflammation (Gurung, Lukens & Kanneganti, 2015). Therefore, the NLRP3 inflammasome is both a consequence of mitochondrial dysfunction and an amplifier of neuroinflammation, establishing a vicious cycle between the two that accelerates the pathological progression of PD. Recent advances further reveal that CNS inflammatory circuits are intimately linked to gut-mediated immune modulation, as microbiota-derived metabolites and barrier perturbations reshape peripheral immune states and transmit pro-inflammatory signals to the brain, thereby embedding gut–immune communication within the broader neurodegenerative cascade of PD (Sampson et al., 2016; Mou et al., 2022). Increasing evidence underscores the critical role of the peripheral immune system in PD pathology, as peripheral blood in PD patients shows elevated levels of pro-inflammatory monocytes and T-cell subsets, with monocytes exhibiting a classical pro-inflammatory phenotype and T-cells primarily differentiating into Th1 and Th17 subtypes, and these immune alterations being strongly linked to increased pro-inflammatory cytokine expression (Contaldi, Magistrelli & Comi, 2022). Genetic variations in the HLA region have been shown to significantly correlate with PD risk. Studies indicate a strong link between HLA risk alleles and α-syn-specific T-cell responses, highlighting the pivotal role of the adaptive immune system in PD pathogenesis (Sulzer et al., 2017). Although current research offers valuable insights into immune-inflammatory mechanisms in PD, understanding longitudinal immune changes and their effects across disease stages remains a significant challenge for developing precise therapeutic strategies (Fig. 2).

MAPKs signaling pathway

MAPKs, crucial intracellular signaling molecules from the serine/threonine protein kinase family, play essential roles in various cellular processes by responding to external stimuli such as growth factors, stress, inflammation, and cellular damage, with these signals being transmitted to the nucleus to regulate cell proliferation, differentiation, apoptosis, and survival, underscoring the vital role of MAPKs in adapting to environmental changes and regulating cellular fate (Guo et al., 2023a). The MAPK signaling pathway functions through a cascade of sequentially activated kinases, encompassing subtypes like extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 MAPK. In PD, aberrant activation of these pathways is strongly linked to the loss of DA neurons as well as oxidative stress and inflammatory responses in neurons (Gil-Martinez et al., 2020). The ERK pathway, a key branch of the MAPK signaling cascade, primarily regulates cell proliferation and survival, with research indicating that the ERK1/2 signaling pathway protects DA neurons from neurotoxins like MPP+ and mitigates neuronal damage in PD by modulating gene expression associated with cell survival and apoptosis (Li et al., 2023b). However, in a PD mouse model induced by 6-hydroxydopamine (6-OHDA), excessive activation of the ERK pathway was observed, with this hyperactivation being modulated by the cAMP/PKA pathway in direct pathway neurons (dSPNs) and calcium signaling mediated by AMPA receptors in indirect pathway neurons (iSPNs), ultimately disrupting motor control through distinct molecular mechanisms and contributing to the characteristic motor symptoms of PD (Mariani et al., 2019). Thus, the ERK pathway exhibits dual roles in PD: it provides neuroprotection under normal conditions but exacerbates disease progression when abnormally activated. This complexity highlights the need for precise timing and method selection in therapeutic interventions. The JNK pathway serves as a critical regulator of intracellular stress responses in the MAPK family. It involves small G proteins, including Rac and Cdc42, that activate downstream kinases, resulting in JNK phosphorylation and activation (Coso et al., 1995). Activated JNK translocates to the nucleus, where it activates transcription factors that induce the expression of pro-apoptotic genes, resulting in progressive neuronal loss (Li et al., 2024). Furthermore, JNK-mediated phosphorylation activates the transcription factor forkhead box protein O1 (FoxO1), a critical mediator of oxidative stress and apoptosis in various cell types, including neurons (Liu et al., 2020). Additionally, the JNK pathway promotes neuroinflammation by activating multiple pro-inflammatory factors, and studies have shown that inhibiting this pathway reduces oxidative stress, inflammation, and neuronal damage associated with rotenone-induced neurodegeneration (Vasudevan Sajini et al., 2024). Similar to JNK, the p38 MAPK pathway is primarily activated by oxidative stress and inflammation-related stimuli, regulating inflammatory responses at both transcriptional and translational levels as a key mediator of neuroinflammation, while also modulating the expression of inflammatory cytokines and stress-response genes through multiple downstream targets (Hwang et al., 2016). Additionally, studies suggest that excessive activation of the p38 MAPK pathway in PD not only exacerbates inflammation but also leads to mitochondrial dysfunction and apoptosis pathways, making cells more susceptible to oxidative stress and further promoting neuronal apoptosis and inflammation (Chen et al., 2018). In summary, activation of the MAPK pathways plays a critical role in driving oxidative stress and neuroinflammation, accelerating the neurodegenerative progression of PD.

The regulation of MAPKs pathways by SCFAs primarily depend on GPCRs. When SCFAs interact with intestinal epithelial cells via GPR41 and GPR43, they activate the ERK1/2 and p38 MAPK signaling pathways, leading to the production of chemokines and cytokines that regulate leukocyte recruitment and effector T-cell activation, with activated T cells disrupting the BBB or directly infiltrating the brain, thereby initiating neuroinflammation and contributing to PD pathology (Kim et al., 2013; Yshii et al., 2022). However, the concentrations of SCFAs in the brain are much lower than those typically used in in vitro studies, which may limit the direct applicability of these findings to physiological conditions. Nevertheless, SCFAs exhibit complex and dual effects, depending on their concentration and context. In a neuroinflammation model using TNF-α-stimulated SH-SY5Y neuroblastoma cells, sodium butyrate (NaB) reduced p38 phosphorylation and decreased the expression of inflammatory markers, including inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), thereby attenuating oxidative stress and inflammation and contributing to neuronal protection (Bayazid et al., 2021). Therefore, we hypothesize that the pro-inflammatory effects of SCFAs may contribute negatively during the early or progressive stages of PD. However, following neuronal damage and neuroinflammation, SCFAs may exert neuroprotective effects by inhibiting MAPK pathways. The underlying mechanisms remain to be elucidated, but targeting SCFA signaling pathways could offer a more precise therapeutic strategy.

NF-κB signaling pathway

The Nuclear Factor kappa B (NF-κB) signaling pathway is a versatile regulatory system widely present in various nervous system cell types, including neurons, oligodendrocytes, microglia, and astrocytes, primarily regulating immune and inflammatory responses while also controlling cell survival and apoptosis (Cildir, Low & Tergaonkar, 2016). NF-κB comprises protein dimers, including p50, p52, p65/RelA, c-Rel, and RelB, with subunit combinations providing specific regulatory functions in different cell types (Salles, Romano & Freudenthal, 2014). Under normal physiological conditions, NF-κB is inhibited by the IκB protein complex, which retains it in the cytoplasm; however, in the pathological environment of PD, external stimuli activate cell surface receptors, triggering a signaling cascade through adaptor proteins that leads to the activation of the IκB kinase (IKK) complex, which phosphorylates IκB, causing its degradation and the release of NF-κB dimers that translocate to the nucleus to initiate the transcription of pro-inflammatory genes (Yshii et al., 2022). Previous studies have shown that persistent neuroinflammation and α-synuclein aggregates in PD activate microglia and elevate pro-inflammatory cytokine levels, leading to excessive activation of the NF-κB pathway, which in turn triggers further pro-inflammatory cytokine release, creating a vicious cycle that exacerbates neuronal damage and death (Dolatshahi et al., 2021; Leandrou et al., 2024). NF-κB activation also plays a critical role in the apoptosis of DA neurons in PD. Under prolonged neuronal stress and oxidative conditions, NF-κB interacts with apoptosis-related proteins like p53 and Bcl-2-associated X protein (Bax), enhancing apoptotic signaling and causing irreversible neuronal damage (Chauhan et al., 2016). While the detrimental effects of NF-κB in PD are well-documented, its complexity and dual roles warrant consideration. Some evidence suggests that NF-κB may have neuroprotective effects under specific conditions, as TNF-α, through the NF-κB pathway, activates downstream complexes such as TNFR1-Associated Death Domain Protein and TNF Receptor-Associated Factor 2 (TRAF2) via TNF receptors, facilitating NF-κB translocation to the nucleus and inducing the expression of anti-apoptotic genes, thereby counteracting apoptosis triggered by cellular stress (Heyninck & Beyaert, 2001). Receptor-interacting proteins (RIPs) and TRAF2 regulate IKK activation, suppress apoptotic signaling, and promote neuronal survival (Zhang et al., 2009). These mechanisms are essential for neuronal development, synaptic plasticity, and acute stress responses, maintaining normal central nervous system function. While the pro-inflammatory and pro-apoptotic roles of the NF-κB pathway in PD are well-researched, its dual functions also suggest potential neuroprotective mechanisms. However, drugs directly targeting NF-κB have demonstrated limited efficacy in PD treatment due to off-target toxicity and poor specificity (Gray et al., 2014). Therefore, SCFAs exert a precise regulatory effect by not only modulating GPR109A receptors to inhibit NF-κB activity but also suppressing HDAC3-mediated acetylation of STAT1 and NF-κB p65, thereby preventing the nuclear translocation of NF-κB p65 and interrupting the amplification of inflammatory cascades (Xu et al., 2022b; Hu et al., 2024). Through these mechanisms, SCFAs not only significantly attenuate inflammatory responses but also offer a targeted immunoregulatory strategy, highlighting their promising therapeutic potential for neuroprotection and anti-inflammatory interventions.

JAK/STAT signaling pathway

The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway is a key mediator of cytokine and growth factor responses, playing a critical role in immune regulation, cell growth, differentiation, and apoptosis, with the Janus kinase (JAK) family (JAK1, JAK2, JAK3, and TYK2) consisting of receptor-associated tyrosine kinases that cooperate with seven STAT proteins (STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6) to regulate cellular functions (Qin et al., 2016). In response to extracellular signals, such as elevated interferon-gamma (IFN-γ) and interleukin-6 (IL-6) levels in PD, JAK is recruited to the cytoplasmic domains of cytokine receptors, activating the pathway (Lashgari et al., 2021). Upon activation, JAK phosphorylates specific tyrosine residues on receptor intracellular domains, creating docking sites for STAT proteins, and phosphorylated STAT proteins dimerize (as homodimers or heterodimers) via Src-homology 2 (SH2) domains before translocating to the nucleus to regulate gene expression by binding specific DNA sequences, while feedback regulators such as suppressor of cytokine signaling (SOCS) and protein inhibitors of activated STAT (PIAS) maintain homeostasis by limiting excessive JAK/STAT activation and preventing pathological consequences (Sarapultsev et al., 2023). In vitro studies reveal that α-synuclein overexpression enhances STAT3 activation in the SNpc, promoting pro-inflammatory gene expression, including MHC II, iNOS, IL-6, and TNF-α in macrophages and microglia, thereby upregulating the JAK/STAT pathway and fostering a neuroinflammatory environment (Qin et al., 2016). The Line 61-PFF mouse model, serving as a platform for studying the neuroinflammatory mechanisms of PD, identifies two pro-inflammatory immune cell clusters, MM4 and T3, which significantly decrease following treatment with the JAK1/2 inhibitor AZD1480, further revealing that these clusters are driven by the JAK/STAT signaling pathway, thereby highlighting the pivotal regulatory role of this pathway in the neuroinflammatory progression of PD (Hong et al., 2024). In PD, ROS activation of the JAK/STAT pathway serves as a critical link between oxidative stress and neuroinflammation. This activation occurs independently of new protein synthesis, highlighting ROS as a direct upstream activator of the JAK/STAT pathway, and ROS-induced JAK/STAT signaling amplifies inflammation, leading to neuronal death and creating a feedforward cycle that perpetuates oxidative stress, STAT activation, neuroinflammation, and neurodegeneration (Simon et al., 1998). Although JAK/STAT signaling is a convergent inflammatory pathway across multiple neurodegenerative disorders, its activation in PD is more tightly interwoven with redox imbalance and α-synuclein–triggered innate immune activation, in contrast to its broader roles in peripheral immune polarization and demyelination in diseases such as multiple sclerosis and Alzheimer’s disease (Sarapultsev et al., 2023). Precisely modulating this pathway to attenuate neuroinflammation without disrupting its physiological roles in cellular defense and repair remains an unresolved therapeutic challenge requiring fine-tuned, context-specific intervention strategies.

In recent years, the inhibitory effects of SCFAs on the JAK/STAT pathway have been widely studied and acknowledged (Ying, Wei & An, 2021). Both in vivo and in vitro studies have demonstrated excessive phosphorylation of JAK2 and STAT3 in MPTP-induced PD mouse models and MPP+-treated PC12 cells, while treatment with SCFAs significantly reduced overactivation of the JAK2/STAT3 pathway, along with notable downregulation of oxidative stress markers and pro-inflammatory cytokines, and the specificity of SCFAs’ effects on the JAK2/STAT3 pathway was further validated by the reversal of their inhibitory effects upon treatment with the JAK2 agonist C-A1, highlighting the critical role of the JAK2/STAT3 axis in mediating the neuroprotective effects of butyrate (Ji et al., 2023). However, the effects of SCFAs are cell-specific, as they can enhance the expression of iNOS and nitric oxide (NO) production in intestinal epithelial cells via JAK/STAT signaling, displaying pro-inflammatory properties, which contrasts sharply with their anti-inflammatory effects in other cell types (Stempelj et al., 2007). While SCFAs have the potential to alleviate neuroinflammation in the brain, their pro-inflammatory effects necessitate a nuanced approach when considering their application as therapeutic agents for PD.

PI3K/Akt signaling pathway

The phosphoinositide 3-kinase (PI3K) family is a central component of this pathway, and PI3K is categorized into three types based on its structure and function; however, research indicates that only Class I PI3Ks exhibit lipid kinase activity in response to growth stimuli, activating protein kinase B (PKB, also known as Akt) (Gupta et al., 2022). Class I PI3K comprises a catalytic subunit (p110) and a regulatory subunit (p85), and under normal conditions, it is activated by upstream molecules such as RTKs or GPCRs through growth factor binding, leading to the conversion of phosphatidylinositol 4,5-bisphosphate (PIP2) into phosphatidylinositol 3,4,5-trisphosphate (PIP3); however, acting as a key signaling molecule, PIP3 recruits and activates downstream effectors such as PDK1 and Akt at the cell membrane, thereby initiating a variety of intracellular biological processes (Long et al., 2021; Gupta & Gaykalova, 2024). Akt, a serine/threonine kinase, inhibits the progressive apoptosis of DA neurons in the substantia nigra by phosphorylating Bcl-2 antagonist and FoxO1, while it also regulates nuclear factor erythroid 2-related factor 2 (Nrf2) to enhance antioxidant enzyme expression, thereby mitigating oxidative stress-induced neuronal damage (Long et al., 2021). Akt also directly phosphorylates glycogen synthase kinase-3β (GSK-3β) at the Ser9 site, inhibiting its activity, while the resulting reduction in GSK-3β activity decreases abnormal phosphorylation of α-synuclein, preventing its aggregation and alleviating PD pathology (Yang et al., 2018). Full activation of Akt requires phosphorylation at Thr308 by PDK1 and at Ser473 by the mTORC2 complex, and once activated, Akt phosphorylates various substrates to regulate multiple cellular processes (Sarbassov et al., 2005). Mammalian target of rapamycin (mTOR) serves as a critical downstream target of Akt, forming the mTORC1 and mTORC2 complexes to regulate cell growth, metabolism, autophagy, and protein synthesis (Gupta et al., 2022). Akt activates mTORC1 by phosphorylating and inhibiting tuberous sclerosis complex 2 (TSC2), and subsequently, mTORC1 phosphorylates S6 kinase 1 (S6K1) and 4E-binding protein 1 (4EBP1), promoting protein synthesis, supporting neuronal survival, and enhancing antioxidant defenses (Wong, 2010). In PD, dysregulation of the PI3K/Akt/mTOR pathway may impair neuronal protein synthesis, compromising the repair and survival of DA neurons (Song, Peng & Zhu, 2021). Moreover, the PI3K/Akt/mTOR pathway serves as a critical negative regulator of autophagy, and inhibition of this process can hinder the clearance of abnormally aggregated α-Syn (Zhang et al., 2021). Therefore, prolonged overactivation of the PI3K/Akt/mTOR pathway may disrupt this essential protective autophagy process, thereby exacerbating PD pathology.

Given the prominent role of the PI3K/Akt signaling pathway in autophagy regulation, researchers have explored its interplay with the Atg5-dependent autophagy pathway, and in NaB-treated mouse neuroendocrine STC-1 cells, Atg5 expression was elevated while the PI3K/Akt/mTOR pathway was significantly suppressed, with this suppression being critical for autophagy activation, while this process not only facilitated the degradation of α-synuclein but also appeared to influence apoptosis and inflammatory responses, offering new insights into potential therapeutic mechanisms for PD (Qiao et al., 2020b). Another study using a rat MCAO model to simulate ischemic brain injury demonstrated that NaB binding to GPR41 activated downstream Gβγ subunits, which in turn attenuated neuronal apoptosis through the PI3K/Akt signaling pathway, providing neuroprotection (Zhou et al., 2021). Additionally, propionate was found to activate the PI3K/Akt signaling pathway, enhancing eNOS phosphorylation and increasing NO production, which reduced oxidative stress-induced damage to DA neurons, alleviated neuronal apoptosis, and subsequently slowed disease progression while improving patient symptoms (Wu et al., 2022). In summary, the potential of SCFAs to regulate the PI3K/Akt signaling pathway in PD warrants further investigation. However, practical application of this strategy must address individual variability and elucidate the complexity of underlying mechanisms to ensure safety and efficacy.

AMPK signaling pathway

AMP-activated Protein Kinase (AMPK) is a critical regulator of cellular energy balance, forming a heterotrimeric complex consisting of a catalytic α subunit and two regulatory subunits, β and γ (Hardie, Carling & Gamblin, 2011). In the early stages of PD, increased oxidative stress exacerbates mitochondrial damage and triggers neuroinflammation (Picca et al., 2020). Under such pathological conditions, ATP consumption rises, leading to elevated levels of AMP and ADP, which bind to the CBS domain of AMPK’s γ subunit and induce conformational changes that expose the Thr-172 site on the α subunit, enhancing phosphorylation by upstream kinases such as liver kinase B1 (LKB1) and calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2), thereby activating AMPK (Mihaylova & Shaw, 2011). Activated AMPK plays a pivotal role in restoring mitochondrial function, regulating energy metabolism, and enhancing neuronal survival in PD. Recent studies reveal that AMPK activation of SIRT1 effectively combats oxidative stress, triggers autophagy, and suppresses neuroinflammation, and in conjunction with peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC-1α), AMPK enhances mitochondrial biogenesis and function, reduces ROS production, and mitigates oxidative stress-induced neuronal apoptosis, with these combined mechanisms contributing significantly to long-term neuronal recovery (Fan et al., 2024; Elesawy et al., 2024). Furthermore, AMPK actively promotes mitophagy by directly phosphorylating Unc-51-like autophagy activating kinase 1 (ULK1), initiating autophagosome formation and the degradation of damaged mitochondria (Hardie, 2011). The PINK1/Parkin pathway plays a central role in this process, with recent studies showing that AMPK regulates the localization of PINK1 mRNA to mitochondria, which is essential for local PINK1 protein translation and the initiation of mitophagy, and a complex formed by the outer mitochondrial membrane protein SYNJ2BP and the RNA-binding protein SYNJ2 anchors PINK1 mRNA to mitochondria, while AMPK phosphorylates the PDZ domain of SYNJ2BP, enhancing its interaction with SYNJ2 and ensuring the stable connection of PINK1 mRNA to mitochondria, thereby facilitating efficient PINK1 protein translation on locally damaged mitochondria and initiating mitophagy to address mitochondrial damage (Hees et al., 2024). Researchers demonstrated that cytarabine enhances PINK1/Parkin-mediated mitophagy via AMPK activation, thereby improving mitochondrial function, reducing oxidative stress, and providing significant neuroprotection in rotenone-induced PD models (Soper et al., 2008). Moreover, recent studies on the AMPK-mTOR-TFEB axis have firmly linked AMPK to α-synuclein degradation, as AMPK inhibits mTOR to initiate autophagy and enhance the nuclear translocation of transcription factor EB (TFEB), a key regulator of lysosome-associated genes, thereby promoting lysosome biogenesis and reducing α-synuclein expression, a finding validated in A53T α-synuclein PD mouse models (Xu et al., 2022a). This discovery opens new therapeutic avenues for previously undruggable diseases, particularly through targeted protein degradation via the AMPK-mTOR-TFEB signaling pathway. However, precisely modulating AMPK signaling to avoid potential side effects remains a key focus for future research.

SCFAs have long been recognized for their potential to improve mitochondrial function and provide neuroprotection through activation of the AMPK pathway, which is significant for mitigating the pathological progression of PD (Tang et al., 2011; Herzig & Shaw, 2018). Cognitive impairment, a frequent no mutant ataxin-3 aggregates, and improved motor function, with the activation of the AMPK pathway being central to these effects, suggesting that SCFAs may similarly benefit PD by enhancing autophagy in diseases with comparable pathological features (Watchon et al., 2024). The protective effects of SCFAs against oxidative stress and mitochondrial dysfunction in IPEC-J2 cells provide compelling evidence for their potential application in PD, as SCFAs activate AMPK to promote mitophagy and alleviate oxidative stress, offering a neuroprotective strategy to slow PD progression. Notably, SCFA-mediated activation of AMPK displays a marked dose-dependent profile, wherein escalating concentrations of SCFAs correlate with increasingly robust AMPK phosphorylation, culminating in amplified anti-inflammatory effect outcomes (Li et al., 2023a). These findings highlight the importance of SCFAs and the AMPK pathway in neurodegenerative disease research, paving the way for novel interventions targeting mitochondrial and cellular health in PD (Li et al., 2022). However, current research has primarily focused on metabolic disease models. Further investigation is needed to elucidate the precise mechanisms and long-term effects of SCFA-mediated AMPK activation in PD.

Nrf2/Keap1/ARE signaling pathway

Nrf2 is a transcription factor that orchestrates cellular antioxidant responses by regulating the expression of various antioxidant and cytoprotective genes, and structurally, Nrf2 contains several highly conserved domains, with the Neh1 domain enabling Nrf2 to form heterodimers with small Maf proteins (MafG, MafK, and MafF) in the nucleus, a crucial step for binding to antioxidant response elements (ARE) in the promoter regions of target genes (Bellezza et al., 2018). The Neh2 domain plays a critical role in Nrf2 regulation by mediating its interaction with Kelch-like ECH-associated protein 1 (Keap1), a 625-amino acid polypeptide also known as cytoskeleton-associated protein 1, which anchors Nrf2 in the cytoplasm and acts as a molecular switch to control its activity (Bryan et al., 2013). Under normal conditions, Nrf2 binds to Keap1 in the cytoplasm to form an inactive complex, with Keap1 targeting Nrf2 for ubiquitination and proteasomal degradation, thereby maintaining Nrf2 at low basal levels and minimizing the transcription of antioxidant genes (Cores et al., 2020). In the progression of PD, oxidative stress and electrophilic compounds modify cysteine residues in the IVR region of Keap1, allowing Nrf2 to evade proteasomal degradation, translocate into the nucleus, form heterodimers with small Maf proteins, and bind to ARE sequences, which activates the transcription of antioxidant enzymes such as γ-glutamylcysteine synthetase (γ-GCS), quinone oxidoreductase 1 (NQO1), and heme oxygenase-1 (HO-1) (Cuadrado et al., 2019).

The activated Nrf2/Keap1/ARE signaling pathway theoretically reduces oxidative stress-induced neuronal damage (Shirgadwar et al., 2023; Shah et al., 2024). However, dysregulation of Nrf2 pathways, particularly interactions with factors like p38, JNK, and Bach1, can lead to insufficient antioxidant gene expression, thereby failing to effectively mitigate oxidative neuronal injury (George et al., 2022). Nevertheless, Nrf2 enhances mitochondrial autophagy by regulating the expression of genes such as PGC-1α (PPAR-γ coactivator-1α), Nrf1, and PINK1, which helps eliminate damaged mitochondria and effectively curtails the production of ROS (Gumeni et al., 2021). Furthermore, experiments with SQSTM1 (p62) plasmid transfection showed that p62 overexpression significantly inhibited ferroptosis in DA neurons by activating the Nrf2/Keap1/ARE pathway, which also regulated mitochondrial autophagy and suppressed ROS generated by iron overload, further demonstrating Nrf2’s key role in maintaining mitochondrial function and alleviating oxidative stress (Yao et al., 2024). Additional studies have shown that Nrf2 regulates the expression of 20S and 26S proteasomes as well as HO-1, facilitating the degradation of α-synuclein aggregates, shortening its half-life, and promoting its clearance, which helps reduce α-synuclein neurotoxicity and slow PD progression (He et al., 2013; Skibinski et al., 2017; Chakkittukandiyil et al., 2022). In inflammatory conditions, Nrf2, stabilized by DJ-1 protein, also plays a significant role in suppressing neuroinflammation (Clements et al., 2006). Nrf2 regulates downstream HO-1 expression, which breaks down heme to produce carbon monoxide (CO) and other byproducts that inhibit NF-κB signaling, and this also activates the anti-inflammatory cytokine IL-10, further mitigating inflammation in PD (Loboda et al., 2016; Ahmed et al., 2017). Moreover, Nrf2 not only reduces the expression and release of pro-inflammatory cytokines, preventing excessive microglial activation, but also effectively suppresses the overactivation of the NLRP3 inflammasome, thereby mitigating the resulting neuroinflammation and ultimately slowing the progression of PD (Rajan et al., 2023; Kaur et al., 2024). Therefore, it is evident that the Nrf2/Keap1/ARE signaling pathway provides multi-faceted protection in PD.

Both in vitro and in vivo studies have demonstrated that butyrate enhances Nrf2 antioxidant activity by inducing its nuclear translocation through HDAC inhibition, and in Nrf2-knockout mouse models, butyrate activates Nrf2 via HDAC inhibition mediated by P300, highlighting butyrate’s critical role in regulating Nrf2 through epigenetic mechanisms in the absence of Nrf2 and suggesting its potential therapeutic value in mitigating oxidative stress and inflammation in PD (Wu et al., 2018). Additionally, evidence from bovine mammary epithelial cells indicates that butyrate promotes Nrf2 nuclear accumulation by activating the GPR109A receptor, which deactivates AMPK signaling, a regulatory mechanism that underscores the diverse pathways through which butyrate modulates Nrf2 activity (Guo et al., 2020). In contrast, fewer studies have investigated propionate. However, evidence from BBB integrity models suggests that propionate promotes Nrf2 nuclear translocation via pathways such as GPR41 activation, while concurrently enhancing the expression of tight junction proteins, maintaining BBB integrity, and reducing neuroinflammation, highlighting the neuroprotective potential of propionate in modulating oxidative stress and preserving BBB function (Fock & Parnova, 2023).