Acetylation Regulates ACSL4 Degradation Through Chaperone‐Mediated Autophagy to Alleviate Intervertebral Disc Degeneration

Abstract Chaperone‐mediated autophagy (CMA) represents a critical lysosomal degradation pathway in the context of intervertebral disc degeneration (IVDD) associated with senescence. This study revealed a novel mechanism of CMA regulation involving targeted degradation of acyl‐CoA synthetase long‐chain family member 4 (ACSL4), which can delay nucleus pulposus cell (NPC) senescence and inhibit IVDD progression. Mechanistic investigations demonstrated that the acetyltransferase KAT2B can facilitate the acetylation of ACSL4 at lysine residues K500, K571, and K692. This post‐translational modification served as a molecular switch, significantly enhancing the affinity between ACSL4 and the CMA recognition chaperone HSPA8, thereby promoting the efficient targeting and degradation of ACSL4 via the CMA pathway. Besides, engineered exosomes are harnessed to deliver the key CMA receptor LAMP2A in an in vivo model, effectively delaying cellular senescence and significantly attenuating IVDD progression. Overall, these findings establish the crucial protective role of CMA in preventing IVDD through the degradation of ACSL4, providing novel insights for developing therapeutic strategies targeting CMA activation to alleviate disc degeneration and associated chronic pain.