Ethyl caffeate restores BNIP3L-dependent mitophagy and mitochondrial function to ameliorate influenza A virus-induced lung injury

Influenza A virus (IAV) infection induces severe lung injury characterized by excessive inflammation and mitochondrial dysfunction, in which impaired mitochondrial clearance plays a crucial role. Ethyl caffeate (EC), a bioactive phenolic compound of dietary origin, exhibits potent anti-inflammatory and antioxidant properties. However, its protective role against IAV-triggered lung damage and mitochondrial quality control dysfunction remains poorly defined. In this study, PR8-induced IAV infection models was established in mice and cells to evaluate the protective effects of EC. EC treatment improved survival outcomes, markedly alleviated lung injury in a manner independent of direct viral inhibition, reduced pro-inflammatory cytokine expression, and improved mitochondrial function. Mechanistically, EC rescued the impaired autophagy flux induced by IAV infection, as evidenced by reduced p62 accumulation and enhanced mitochondrial clearance, and this effect required intact lysosomal degradation activity. Proteomic analysis further identified BNIP3L as a key regulator, and genetic knockdown of BNIP3L largely abolished EC-mediated protective phenotypes. EC significantly upregulated BNIP3L expression to promote mitochondrial clearance and maintain mitochondrial homeostasis. Metabolomic analysis showed that EC markedly reshaped host metabolic profiles associated with mitochondrial function in lung, with trigonelline identified as a key metabolite upon EC intervention. Functional experiments demonstrated that trigonelline recapitulated EC-like protective effects by facilitating autophagosome-lysosome fusion to restore BNIP3L-dependent mitochondrial clearance and attenuating inflammatory responses both in vitro and in vivo . Overall, EC alleviates IAV-induced lung injury by restoring BNIP3L-mediated mitochondrial clearance and mitochondrial homeostasis. Trigonelline serves as a functional metabolite and metabolic signature of this protective process, highlighting a potential link between plant-derived phenolic compounds, mitochondrial clearance regulation, and host metabolic reprogramming during viral infection.