Inhibition of AKR1C3 attenuates sepsis-induced acute liver injury by blocking the TRAF6/NF-κB pathway and NLRP3 inflammasome activation.

Acute liver injury (ALI), a life-threatening complication of sepsis in critically ill patients, remains a significant clinical challenge with limited therapeutic options. While Aldo-Keto Reductase Family 1 Member C3 (AKR1C3), a key regulator of inflammatory and immune responses, has emerged as a critical regulator in sepsis progression, its functional role and molecular mechanisms in sepsis-induced ALI remain poorly defined. This study aimed to investigate the therapeutic potential of AKR1C3 inhibition and elucidate its underlying mechanisms in ALI pathogenesis. Using a cecal ligation and puncture (CLP)-induced sepsis murine model, we observed significant upregulation of AKR1C3 protein expression in liver tissues, correlating with disease severity. Pharmacological inhibition of AKR1C3 dramatically ameliorated CLP-induced hepatic pathological damage, restored liver function biomarkers, and attenuated systemic inflammation. Mechanistically, AKR1C3 suppression inhibited hepatocyte pyroptosis by blocking NOD-like receptor family, pyrin domain-containing protein 3 (NLRP3) inflammasome activation and reduced pro-inflammatory cytokine release via inactivation of the nuclear factor kappa-B (NF-κB) signaling pathway. Further molecular studies revealed that AKR1C3 potentiates NF-κB activity by interacting with TNF receptor-associated factor 6 (TRAF6) and enhancing its ubiquitination, thereby facilitating downstream inflammatory cascades. Collectively, our findings identify the AKR1C3/TRAF6/NF-κB axis as a novel regulatory pathway driving sepsis-associated ALI and propose AKR1C3 inhibition as a promising therapeutic strategy for this critical condition.