Chaperone-Mediated Autophagy Reactivation Protects Against Severe Acute Pancreatitis-Associated Liver Injury Through Upregulating Keap1/Nrf2 Signaling Pathway and Inhibiting NLRP3 Inflammasome Activation.

Abstract

Acute liver injury (ALI) is a vital factor in the early progression of severe acute pancreatitis (SAP). It exacerbates systemic inflammation, impairs the liver's capacity to clear inflammatory mediators and cytokines, and contributes to systemic organ dysfunction syndrome (SODS). However, the mechanisms driving SAP-associated liver injury (SAP-ALI) are poorly understood, and effective therapeutic options remain limited. Chaperone-mediated autophagy (CMA), a selective form of autophagy, plays an essential role in reducing inflammation and oxidative stress by clearing damaged or dysfunctional proteins. This study examines the role of CMA in SAP-ALI and evaluates its therapeutic potential. In a sodium taurocholate-induced SAP-ALI rat model, CMA dysfunction was observed, characterized by reduced LAMP2A expression and the accumulation of CMA substrate proteins in pancreatic and hepatic tissues. The activator AR7 successfully restored CMA function, enhanced anti-inflammatory and antioxidant responses, and mitigated pancreatic and liver damage in SAP rat. In contrast, the CMA inhibitor PPD exacerbated liver injury, underscoring CMA's protective role in SAP-ALI. Mechanistic analyses demonstrated that CMA reactivation activated the Keap1/Nrf2 signaling pathway, leading to increased expression of antioxidant-related genes and suppression of NLRP3 inflammasome activation. Specifically, the protective effects of AR7-induced CMA activation were significantly reversed by the Nrf2 inhibitor ML385, which inhibited Nrf2 signaling and its associated protein levels. These findings show AR7-induced CMA reactivation as a promising therapeutic strategy for SAP-ALI, primarily through its enhancement of Keap1/Nrf2-regulated antioxidant pathways and inhibition of NLRP3 inflammasome activation.