Caffeic Acid Acts as a Potent Senomorphic and Alleviates Inflammation and Lung Fibrosis by Covalently Targeting Annexin A5 Protein in Mice

ABSTRACT The accumulation of senescent cells and their secretion of senescence‐associated secretory phenotype (SASP) play important roles in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Small molecules, known as senolytics or senomorphics, have been effective in targeting senescent cells. Although senolytic drugs have been well‐studied in pulmonary fibrosis, senomorphics with defined protein targets and potential applications are rarely investigated. In this study, we identified a widely sourced natural product, caffeic acid (CA), to act as a potent senomorphic that effectively inhibits the secretion of SASP in senescent lung cells. We demonstrated that the covalent binding of CA to Annexin A5 protein triggered its degradation, PKCθ deactivation, and the inhibition of the NF‐κB inflammatory pathway in senescent cells. Notably, CA exhibited a promising effect in limiting inflammation in the lung and circulatory system, alleviating pulmonary pathology, and improving physical function in a bleomycin‐induced pulmonary fibrosis mouse model. Our investigation suggests that Annexin A5 could be used as the target for the precise intervention of aging‐related diseases such as IPF.