Sphingolipid-Neuroinflammation Axis in Parkinson's Disease: Focus on S1P/SPHK1-NF‑κB Signaling.

Parkinson's disease (PD) is the second most common neurodegenerative disorder worldwide. Its core pathological features comprise the selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), abnormal aggregation of α‑synuclein (α‑syn) into Lewy bodies, and progressive amplification of neuroinflammation, mitochondrial dysfunction, oxidative stress and lipid metabolism disorders. As a key bioactive sphingolipid, sphingosine‑1‑phosphate (S1P) is synthesized by sphingosine kinase 1 (SPHK1) and regulates immune activation, cell survival and inflammatory responses through intracellular signaling and binding to S1P receptors (S1PR1‑5). Nuclear factor‑κB (NF‑κB) is a key transcription factor closely implicated in the regulation of neuroinflammatory responses, modulating pro‑inflammatory cytokine release, microglial polarization and neuronal apoptosis. Cumulative clinical and preclinical studies have verified elevated S1P levels and activated SPHK1 in PD patients, accumulating data support a correlative link between the S1P/SPHK1‑NF‑κB signaling axis and α‑syn pathology, microglial overactivation, neuroinflammation and dopaminergic neuron degeneration, while multiple mechanistic ambiguities remain unresolved, though several mechanistic ambiguities and translational hurdles remain unaddressed. This review systematically outlines the molecular basis and cell‑specific mechanisms of this axis, its crosstalk with α‑syn aggregation, mitochondrial damage, blood‑brain barrier (BBB) leakage and gut‑brain axis disturbance during PD progression. We further objectively summarize the potential of this axis as auxiliary diagnostic biomarker and druggable therapeutic target, alongside prominent bottlenecks including insufficient detection standardization, interspecies drug response discrepancy and unsatisfactory clinical transformation of preclinical compounds, as well as pending core scientific questions restricting subsequent research advancement. Collectively, this review provides a balanced theoretical framework for exploring PD pathogenesis and developing precise therapy, with critical discussion on existing limitations to guide follow-up basic and translational investigations.