Hesperetin ameliorates APAP-induced liver injury by activating a PKC-TFEB axis.

Abstract

Acetaminophen (APAP) overdose is a leading cause of drug-induced liver injury, driven by oxidative stress and disruption of mitochondrial and lysosomal homeostasis. While transcription factor EB (TFEB) is a known master regulator of autophagy and antioxidant pathways, the upstream mechanism that triggers its activation during APAP hepatotoxicity remains unclear. Here, we demonstrate that the citrus flavonoid hesperetin orchestrates a PKC-TFEB signaling pathway to simultaneously mitigate oxidative damage and restore organelle function in APAP-induced liver injury. Hesperetin enhanced TFEB nuclear translocation and transcriptional activity, thereby restoring autophagic clearance of APAP-protein adducts and mitochondrial biogenesis, as well as SQSTM1/p62-dependent noncanonical NFE2-like bZIP transcription factor 2 (NFE2L2/NRF2) activation to protect against APAP-induced liver injury. Mechanistically, hesperetin directly targeted and activated protein kinase C (PKC), preventing its degradation and thus leading to TFEB activation. Our study identifies hesperetin as a novel small-molecule activator of a PKC-TFEB pathway, which couples NRF2-dependent redox balance with mitochondrial-lysosomal repair to counteract APAP toxicity. These findings propose a new strategy for treating oxidative-stress-driven liver injury by targeting TFEB-mediated homeostasis.

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