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Previous clinical studies showed that YHJF improves Sequential Organ Failure Assessment (SOFA) scores and modulates gut microbiota in elderly patients with pneumonia-associated sepsis. However, the mechanism by which YHJF protects against sepsis-associated acute lung injury (SALI) remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A murine SALI model was established by cecal ligation and puncture (CLP). Therapeutic effects were evaluated by histopathology, micro-CT, pulmonary function assessment, and ELISA. Mechanistic studies included proteomic analysis of lung tissues and LPS-stimulated MH-S macrophages, pharmacological modulation with Mdivi-1 and urolithin A (UA), macrophage-epithelial co-culture, HPLC fingerprinting, UPLC-HRMS, and molecular docking.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>YHJF significantly improved 7-day survival and ameliorated lung injury, pulmonary edema, respiratory dysfunction, and systemic inflammation in mice with CLP-induced SALI. Proteomic profiling and subsequent functional assays suggested that enhanced mitophagy in macrophages represents a central protective mechanism. In vivo, YHJF increased autophagosome formation and PINK1\/Parkin co-localization in BALF-derived alveolar macrophages. In vitro, YHJF restored mitochondrial homeostasis by activating PINK1\/Parkin-dependent mitophagy in macrophages. This was accompanied by reduced cytoplasmic mtDNA leakage, downregulated cGAS expression, and suppression of the STING\u2013TBK1\u2013IRF3 pathway and subsequent type I interferon responses. Pharmacological inhibition of mitophagy with Mdivi-1 abolished these protective effects of YHJF, whereas activation with UA augmented them, demonstrating that mitophagy is necessary for YHJF-mediated protection. In a macrophage\u2013epithelial co-culture system, YHJF-treated macrophages alleviated LPS-induced apoptosis in MLE-12 alveolar epithelial cells. Furthermore, chemical analysis integrated with molecular docking identified aloe-emodin, rhein, and genistein as candidate bioactive constituents of YHJF that likely contribute to its regulation of macrophage mitophagy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>YHJF protects against SALI by restoring macrophage mitophagy and suppressing mtDNA-STING-mediated inflammatory signalling. These findings support YHJF as a potential therapeutic strategy for sepsis-associated lung injury.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13020-026-01475-0","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T09:23:03Z","timestamp":1785835383000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Yiqi Huoxue Jiedu formula protects against sepsis-associated lung injury by modulating macrophage mitophagy and mtDNA-STING signaling"],"prefix":"10.1186","volume":"21","author":[{"given":"Shuqi","family":"Ma","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiusha","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingnan","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruifeng","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaotu","family":"Xi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuoxu","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaiqiang","family":"Zhong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suyi","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,4]]},"reference":[{"key":"1475_CR1","doi-asserted-by":"publisher","DOI":"10.1016\/j.abb.2024.110229","volume":"763","author":"M Abdelnaser","year":"2025","unstructured":"Abdelnaser M, et al. 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