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Interferon regulatory factor 7 (IRF7) is an immune regulatory factor whose role in lipid metabolism and autophagy has been increasingly studied in peripheral tissues. However, the role of IRF7 in microglial lipophagy (a selective autophagic process that targets LDs) and poststroke functional recovery remains unexplored. In this study, using a mouse photothrombotic ischemia (PTI) model, we observed that microglia in the peri-infarct region displayed persistent lipophagy impairment and LD accumulation for up to 21 days. Reanalysis of the single-cell RNA sequencing (scRNA-seq) dataset revealed that an\n                    <jats:italic>Irf7<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>high<\/jats:italic>\n                    <\/jats:sup>\n                    microglial MG1 subcluster (disease-associated microglia) was significantly associated with autophagy and lipid metabolism poststroke. Furthermore, microglial\n                    <jats:italic>Irf7<\/jats:italic>\n                    conditional knockout (\n                    <jats:italic>Irf7<\/jats:italic>\n                    cKO) mice exhibited a significant rescue of lipophagy impairment and an alleviation of the ensuing LD accumulation in microglia, accompanied by enhanced synaptic plasticity and motor functional recovery during the subacute phase poststroke. Consistently, in the 15-month-old distal middle cerebral artery occlusion (dMCAO) model,\n                    <jats:italic>Irf7<\/jats:italic>\n                    cKO mice also displayed similar improvements. Similar results were also observed in vitro. Mechanistically,\n                    <jats:italic>Gnai2<\/jats:italic>\n                    was identified as a positively regulated transcriptional target of IRF7. In BV2 cells and primary microglia,\n                    <jats:italic>Gnai2<\/jats:italic>\n                    knockdown mitigated lipopolysaccharide (LPS)-induced lipophagy impairment, thereby reducing LD accumulation. This treatment also increased the level of phosphatidylcholine (PC), a key lipid for stabilizing small LDs as well as promoting autophagosome formation and autophagic flux. Consistently, microglial\n                    <jats:italic>Irf7<\/jats:italic>\n                    deletion or knockdown attenuated stroke- or LPS-induced PC reduction both in vivo and in vitro. Furthermore, exogenous supplementation with CDP-choline, an intermediate in PC synthesis, alleviated LD accumulation and lipophagy impairment, thereby improving motor function. Additionally, delayed administration of an inhibitor of stimulator of interferon genes (STING, an upstream target of IRF7) replicated the beneficial effects observed in\n                    <jats:italic>Irf7<\/jats:italic>\n                    cKO mice, and its effects were not further enhanced by microglial\n                    <jats:italic>Irf7<\/jats:italic>\n                    deletion. Taken together, these novel findings reveal that persistent impairment of microglial lipophagy is a key contributor to poststroke LD accumulation, and that IRF7 is involved in this process through direct transcriptional activation of\n                    <jats:italic>Gnai2<\/jats:italic>\n                    , which reduces the PC levels. Suppressing IRF7 with a STING inhibitor is a potential strategy for modulating microglial lipid metabolism and promoting functional recovery following stroke.\n                  <\/jats:p>","DOI":"10.1186\/s12974-026-03902-3","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T08:14:06Z","timestamp":1781684046000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Microglial IRF7-induced lipophagy impairment aggravates lipid droplet overload and impedes neurological recovery after ischemic stroke"],"prefix":"10.1186","volume":"23","author":[{"given":"Jing","family":"Yin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Lu","family":"Miao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue-Fang","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Jie","family":"Zhai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Ren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cai-Hong","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui-Feng","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang-Nan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Jun","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1021-1800","authenticated-orcid":false,"given":"Yan-Ying","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,17]]},"reference":[{"issue":"10459","key":"3902_CR1","doi-asserted-by":"publisher","first-page":"1265","DOI":"10.1016\/S0140-6736(24)01410-7","volume":"404","author":"TN Nguyen","year":"2024","unstructured":"Nguyen TN, Abdalkader M, Fischer U, et al. 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