Hesperetin Alleviates Bleomycin‐Induced Pulmonary Fibrosis by Modulating Cellular Senescence and Promoting Impaired Autophagy in a CISD2‐Dependent Manner

Pulmonary fibrosis is an age-related disease marked by progressive lung function decline and high mortality, with limited treatment options. Hesperetin, a citrus-derived flavonoid with antioxidant and anti-aging properties, has not been thoroughly investigated for its potential in pulmonary fibrosis. This study evaluated the prophylactic potential of hesperetin in pulmonary fibrosis in vivo and in vitro. In vivo experiments demonstrated that hesperetin can significantly reduce cellular senescence in bleomycin-induced pulmonary fibrosis. Activation of Nrf2 signaling was involved in inhibiting cellular senescence and oxidative stress in A549 cells treated with hesperetin. We found that the deficiency of CISD2 contributed to bleomycin-induced pulmonary fibrosis and was associated with the protective effects of hesperetin, which bound with high affinity to CISD2. Meanwhile, overexpression of CISD2 improved cellular senescence induced by bleomycin in vitro. This study further highlighted that the cellular senescence induced by bleomycin was associated with impaired autophagy, which might be related to the inhibition of the CISD2/BECN1 pathway through bioinformatics analysis. Additionally, hesperetin was found to restore bleomycin-induced impaired autophagy by modulating the CISD2/BECN1 pathway. Notably, the protective effects of hesperetin against pulmonary fibrosis were diminished following CISD2 knockdown. Collectively, these findings suggest that hesperetin ameliorates bleomycin-induced pulmonary fibrosis through inhibiting cellular senescence and attenuating impaired autophagy in a CISD2-dependent manner.