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Recent preclinical trials established that senolytic drugs, which target survival mechanisms of senescent cells, can effectively intervene in age\u2010related pathologies. In contrast, senomorphic agents inhibiting SASP expression while preserving the survival of senescent cells have received relatively less attention, with potential benefits hitherto underexplored. By revisiting a previously screened natural product library, which enabled the discovery of procyanidin C1 (PCC1), we noticed pyrroloquinoline quinone (PQQ), a redox cofactor that displayed remarkable potential in serving as a senomorphic agent. In\u00a0vitro data suggested that PQQ downregulated the full spectrum expression of the SASP, a capacity observed in several stromal cell lines. Proteomics data supported that PQQ directly targets the intracellular protein HSPA8, interference with which disturbs downstream signaling and expression of the SASP. PQQ restrains cancer cell malignancy conferred by senescent stromal cells in culture while reducing drug resistance when combined with chemotherapy in anticancer regimens. In preclinical trials, PQQ alleviates pathological symptoms by preventing organ degeneration in naturally aged mice while reserving senescent cells in the tissue microenvironment. Together, our study supports the feasibility of exploiting a redox\u2010active quinone molecule with senomorphic capacity to achieve geroprotective effects by modulating the SASP, thus providing proof\u2010of\u2010concept evidence for future exploration of natural antioxidant agents to delay aging and ameliorate age\u2010related conditions. Prospective efforts are warranted to determine long\u2010term outcomes and the potential of PQQ for the intervention of geriatric syndromes in clinical settings.<\/jats:p>","DOI":"10.1111\/acel.70138","type":"journal-article","created":{"date-parts":[[2025,6,20]],"date-time":"2025-06-20T02:18:57Z","timestamp":1750385937000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Pyrroloquinoline Quinone Is an Effective Senomorphic Agent to Target the Pro\u2010Inflammatory Phenotype of Senescent Cells"],"prefix":"10.1111","volume":"24","author":[{"given":"Birong","family":"Jiang","sequence":"first","affiliation":[{"name":"School of Pharmacy, Institute of Aging Medicine Binzhou Medical University  Yantai Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongwei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Center for Single\u2010Cell Omics, School of Public Health Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qixia","family":"Xu","sequence":"additional","affiliation":[{"name":"Center for Single\u2010Cell Omics, School of Public Health Shanghai Jiao Tong University School of Medicine  Shanghai China"},{"name":"CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health Chinese Academy of Sciences  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhirui","family":"Jiang","sequence":"additional","affiliation":[{"name":"Center for Single\u2010Cell Omics, School of Public Health Shanghai Jiao Tong University School of Medicine  Shanghai China"},{"name":"CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health Chinese Academy of Sciences  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2292-8884","authenticated-orcid":false,"given":"Ruikun","family":"He","sequence":"additional","affiliation":[{"name":"Institute of Nutrition and Health By\u2010Health Co., Ltd.  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