Reversal of Myofibroblast Apoptosis Resistance and Collagen Deposition by Phaseoloidin-Induced Autophagy Attenuates Pulmonary Fibrosis

<b>Background and Objectives</b>: Myofibroblast apoptosis resistance and excessive extracellular matrix (ECM) deposition are central drivers of the irreversibility of pulmonary fibrosis, and both are mechanistically linked to autophagy impairment. <i>Phaseoloidin</i> is a bioactive compound derived from <i>Entada phaseoloides</i>. This study aimed to investigate the therapeutic potential of <i>Phaseoloidin</i> in bleomycin-induced pulmonary fibrosis and its underlying mechanisms. <b>Methods</b>:In vivo, the antifibrotic effects of <i>Phaseoloidin</i> were evaluated using a bleomycin-induced pulmonary fibrosis mouse model in male C57/BL mice. To further elucidate the mechanisms by which <i>Phaseoloidin</i> counteracts fibrosis, in vitro experiments were conducted using primary lung fibroblasts. <b>Results</b>: In vitro experiments showed that <i>Phaseoloidin</i> could activate the AMPK/mTOR pathway in autophagy-deficient myofibroblasts, effectively reversing autophagic defects and promoting collagen degradation. This autophagy activation selectively degraded PTPN13, a negative regulator of apoptosis, thereby enhancing the sensitivity of myofibroblasts to FasL-induced apoptosis and further facilitating fibrosis resolution. After AMPK gene knockout, the pro-autophagic effect of <i>Phaseoloidin</i> completely disappeared, and both collagen clearance and apoptosis recovery were blocked. In vivo experiments confirmed that <i>Phaseoloidin</i> exerted antifibrotic effects by activating AMPK-mediated autophagy in myofibroblasts, which significantly ameliorated pulmonary fibrosis. <b>Conclusions</b>: <i>Phaseoloidin</i> exerts a dual mechanism by activating AMPK-mediated autophagy in myofibroblasts: first, degrading PTPN13 to reverse myofibroblast apoptosis resistance; second, enhancing ECM turnover. These findings indicate that <i>Phaseoloidin</i> is a promising novel therapeutic candidate for pulmonary fibrosis.