TFEB-nuclear translocation promotes BNIP3-mediated mitophagy and alleviates oxidative stress and ferroptosis in acute pancreatitis.

Mitophagy, oxidative stress, and ferroptosis are critical processes in the development of acute pancreatitis (AP). Transcription factor EB (TFEB), a key regulator of autophagy and lysosomal biogenesis, plays a central role in the pathogenesis of AP. However, its specific regulatory mechanisms within the mitophagy-oxidative stress-ferroptosis network remain incompletely understood. This study investigated the therapeutic potential of ginkgetin (GK), a natural TFEB activator, in AP. The results demonstrated that GK activated TFEB and subsequently significantly alleviated pathological damage in AP in vivo and effectively inhibited acinar cell death in vitro. Further mechanistic studies revealed that TFEB activation markedly improved impaired autophagic flux in AP, enhanced mitophagy, and simultaneously suppressed ferroptosis and oxidative stress. Specifically, TFEB upregulated the expression of the lysosomal marker LAMP1 to restore autophagy-lysosome function and induced the expression of BNIP3, a key mitophagy receptor, thereby enhancing mitochondrial quality control, restoring mitochondrial function, and ultimately mitigating oxidative stress and ferroptosis. Functional experiments confirmed that TFEB exerts its protective effects through nuclear translocation. When nuclear translocation was blocked by a C270S mutation-a mutation that disrupts TFEB dissociation from 14-3-3 proteins and subsequent nuclear localization-TFEB's regulatory roles in autophagy, mitophagy, ferroptosis, and oxidative stress were significantly inhibited. This study elucidates that TFEB, through nuclear translocation, not only restores basal autophagy but also enhances mitophagy, thereby collectively inhibiting oxidative stress and ferroptosis and alleviating the progression of AP. These findings provide a novel therapeutic strategy for AP.