{"id":522,"title":"Mevalonate pathway regulates double-negative regulatory T cell stability in metabolic dysfunction–associated steatotic liver disease","title_zh":"甲羟戊酸通路调控代谢功能障碍相关脂肪性肝病中双阴性调节性T细胞的稳定性","url":"https://doi.org/10.1126/sciadv.aeb8568","doi":"10.1126/sciadv.aeb8568","pmid":null,"journal":"Science Advances","kind":"paper","lang":"en","published_at":"2026-11-06T00:00:00+00:00","fetched_at":"2026-11-08T03:45:21+00:00","authors":["Hua Jin","Xiyu Wang","Longyang Zhou","Xinjie Zhong","Yunxiong Wei","Xiaotong Han","Nan Xu","Peiyang Fang","Zihan Zhang","Xiaonan Du","Mengyi Li","Songlin Wang","Zhongtao Zhang","Guangyong Sun","Dong Zhang"],"primary_topic":"ethics-policy","topics":[{"slug":"ethics-policy","score":4.0,"hits":["regulatory"]},{"slug":"repro-immunology","score":3.0,"hits":["regulatory t cell"]},{"slug":"repro-aging","score":1.0,"hits":["mitochondrial"]}],"topic_score":4.0,"preference_score":0.0,"preference_labels":[],"llm_score":48.0,"final_score":56.0,"score_dims":{"novelty":72,"rigor":75,"impact":30,"relevance":12,"translation":25},"recommend_reason":"机制研究扎实（小鼠与患者样本、过继转移验证），但主题为MASLD肝脏免疫代谢，与生殖医学、辅助生殖及胚胎多组学无直接关联，仅对生殖免疫中Treg代谢调控有间接参考价值。","keywords":["甲羟戊酸通路","HMGCR","双阴性调节性T细胞","MASLD","香叶基香叶基化","RAC1"],"selected":0,"story_id":12,"llm_provider":"deepseek","llm_model":"deepseek-flash","llm_effort":"low","source_key":"crossref-cns","source_name":"Crossref · CNS 与大子刊新上线（领域过滤）","source_tier":1,"mention_count":1,"has_interpretation":false,"journal_key":"sci-adv","journal_tier":"cns-sub","journal_if":11.7,"is_mock":false,"summary_zh":"研究在代谢功能障碍相关脂肪性肝病（MASLD）小鼠与患者中观察到，双阴性调节性T细胞（DNTreg）的甲羟戊酸通路及限速酶HMGCR显著下调，且与细胞活力及免疫抑制功能受损相关。机制上，MASLD肝脏富集的花生四烯酸抑制HMGCR表达；其下游产物GGPP介导RAC1香叶基香叶基化，促进RAC1与线粒体CLPX蛋白酶互作，从而增强线粒体功能与免疫调节活性。过继转移Pggt1b+/- DNTreg疗效弱于野生型，提示甲羟戊酸代谢介导的香叶基香叶基化对DNTreg抑制功能与免疫稳态至关重要。","summary":"Lipid metabolism dysfunction and immune imbalance are critical pathogenic drivers of metabolic dysfunction–associated steatotic liver disease (MASLD). Double-negative regulatory T cells (DNTreg) are important immune regulatory cells that maintain liver immune homeostasis. However, their survival and function are compromised in MASLD. Herein, we found that mevalonate pathway and its rate-limiting enzyme HMG-CoA reductase (HMGCR) were significantly down-regulated in DNTreg from both mice and patients with MASLD, correlating with impaired DNTreg viability and immunosuppressive function. Arachidonic acid is enriched in MASLD liver and inhibits DNTreg HMGCR expression. Geranylgeranyl pyrophosphate (GGPP), a downstream product of HMGCR, mediates RAC1 geranylgeranylation, which facilitates its interaction with mitochondrial CLPX protease, thereby enhancing mitochondrial function and immunoregulatory activity of DNTreg. Adoptive transfer of Pggt1b +/− DNTreg into MASLD mice demonstrated significantly diminished therapeutic efficacy compared with wild-type DNTreg. In conclusion, mevalonate metabolism–mediated geranylgeranylation is essential for the suppressive activity and immune homeostasis of DNTreg in MASLD.","interpretation_basis":null,"fulltext_status":null,"interpretation":null,"fulltext":{"available":false,"status":null,"reason":"尚未抓取全文（未入选、分数未达阈值，或还没跑 fulltext 步骤）","pmcid":null,"license":null,"chars":0,"source":null,"fetched_at":null}}