Docosahexaenoic Acid Protects Schwann Cells Against Palmitic Acid–Induced Lipotoxicity by Modulating Autophagy, ER Stress, and Lipid Handling

Elevated saturated fatty acids, such as palmitic acid (PA), induce lipotoxicity in peripheral nerve cells, a pathological feature of metabolic disorders such as type 2 diabetes and obesity that are frequently associated with neuropathic pain (NP). PA overload elicits a maladaptive stress response characterized by endoplasmic reticulum (ER) stress, disrupted intracellular calcium homeostasis, and impaired autophagic flux, ultimately promoting cell death. Although omega-3 polyunsaturated fatty acids such as docosahexaenoic acid (DHA) protect against PA-induced lipotoxicity (PA-LTx), the mechanisms linking lipid handling, ER stress, and autophagy in Schwann cells remain poorly defined. Here, we investigated how PA and DHA regulate autophagic flux, ER stress signaling, and fatty acid-binding protein 5 (FABP5)-dependent lipid trafficking in immortalized Schwann cells (ISCs). PA exposure (300 µM PA:150 µM BSA, 24-48 h) significantly reduced cell viability, impaired autophagic flux as indicated by LC3-II and p62 accumulation, disrupted autophagosome-autolysosome balance, and increased susceptibility to autophagic inhibition by chloroquine. DHA co-treatment (50 µM) preserved cell viability, restored autophagic flux, and normalized autophagosome-autolysosome fusion. Mechanistically, PA induced ER stress marked by increased CHOP, ATF4, and Xbp1 expression, along with progressive ER calcium depletion, whereas DHA suppressed these responses and stabilized calcium homeostasis. Building on prior evidence that FABP5 protects neuron-like cells from PA-LTx, we identified a regulatory role for FABP5 in Schwann cells. PA robustly induced FABP5 expression, which was normalized by DHA and modulated by pharmacological manipulation of autophagy. FABP5 silencing exacerbated PA-induced ER stress, triggered a dysfunctional compensatory autophagy response, and impaired DHA-induced lipid droplet formation. Collectively, these findings demonstrate that functional autophagy and FABP5-dependent lipid buffering are critical adaptive responses to lipotoxic stress in Schwann cells, highlighting these pathways as potential therapeutic targets for NP-associated metabolic neuropathies.