STAT6 Activation Exacerbates Ferroptosis in Airway Epithelium by Inhibiting PRKN‐Mediated Mitophagy in Pulmonary Fibrosis

Abstract Pulmonary fibrosis (PF) remains a clinically intractable condition with limited therapies. Ferroptosis has emerged as a critical driver of PF. The previous study demonstrates that increased secretion of tissue plasminogen activator from ferroptotic airway epithelial cells contributes to PF progression in a paracrine manner. Herein, the indispensable role of signal transducer and activator of transduction 6 (STAT6) is further elucidated in maintaining airway epithelial homeostasis during PF and uncovers a novel mechanism by which STAT6 regulates mitophagy to modulate ferroptosis. Specifically, mitophagy is induced during PF along with STAT6 activation, and deficiency of STAT6 significantly alleviates epithelial ferroptosis and PF. Mechanistically, STAT6 directly binds to the parkin RBR E3 ubiquitin protein ligase (PRKN) promoter region at the site (−990 to −976), inhibiting PRKN transcription and thereby impairing mitophagy. Consistently, lentivirus‐mediated PRKN interference in both wild‐type and STAT6 knockout mice aggravates ferroptosis and PF. Furthermore, virtual screening identifies rifabutin as a potential STAT6 inhibitor, that exhibits therapeutic effects against PF both in vivo and in vitro. Collectively, these findings reveal an unreported mechanism by which STAT6 promotes PF by inhibiting PRKN‐mediated mitophagy in the airway epithelium. Rifabutin is further identified and validated as a promising STAT6 inhibitor to alleviate PF, offering new insights into therapy development.