{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T10:18:25Z","timestamp":1785406705694,"version":"3.56.0"},"reference-count":223,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T00:00:00Z","timestamp":1774915200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"High-Level Talent Cultivation Program for Postgraduates at Xizang University","award":["2025-GSP-S156\/00061359"],"award-info":[{"award-number":["2025-GSP-S156\/00061359"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["32270760"],"award-info":[{"award-number":["32270760"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"award":["32270760"],"award-info":[{"award-number":["32270760"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Xizang Natural Science Foundation","award":["XZ202401ZR0010"],"award-info":[{"award-number":["XZ202401ZR0010"]}]},{"DOI":"10.13039\/501100020771","name":"Young Scientists Fund of the National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82400235"],"award-info":[{"award-number":["82400235"]}],"id":[{"id":"10.13039\/501100020771","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>The female immune system operates within an evolutionary stability-plasticity trade-off, where the physiological demands of pregnancy necessitate a considerable degree of regulatory T cell (Treg) plasticity. This essential flexibility, however, inherently lowers the threshold for autoimmune dysregulation. Recent mechanistic evidence has identified Xist ribonucleoprotein complexes as female-specific autoantigens that constitutively sensitize innate sensors, thereby establishing an intrinsic state of autoimmune priming. This review introduces the Metabolic Calibration Hypothesis, proposing that commensal microbiota-derived metabolites function as essential extrinsic stabilizers specifically required to maintain female immune homeostasis. Beyond canonical short-chain fatty acid signaling, we synthesize emerging evidence regarding host-microbiota metabolic integration, emphasizing the roles of histone lactylation in the reproductive tract and the ligand-specific activation of nuclear receptors by secondary bile acids in orchestrating Treg fate. We posit that female immune pathologies, ranging from systemic autoimmunity to gynecologic malignancies, represent a context-dependent dysregulation or co-option of this metabolic calibration. Ultimately, we discuss the clinical necessity of transitioning from generic biotic interventions toward Sexual Dimorphic Metabotyping, providing a precision framework to restore physiological tolerance and manage sex-biased immune pathologies.<\/jats:p>","DOI":"10.3390\/biology15070558","type":"journal-article","created":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T09:26:12Z","timestamp":1775121972000},"page":"558","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Metabolic Calibration of Female Immune Plasticity: From X-Linked Vulnerability to Precision Metabotyping"],"prefix":"10.3390","volume":"15","author":[{"given":"Zhengsha","family":"Huang","sequence":"first","affiliation":[{"name":"College of Medicine, Xizang University, Lhasa 850000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianwei","family":"Ren","sequence":"additional","affiliation":[{"name":"College of Medicine, Xizang University, Lhasa 850000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qipeng","family":"Shu","sequence":"additional","affiliation":[{"name":"College of Medicine, Chongqing University, Chongqing 400030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuntao","family":"Tang","sequence":"additional","affiliation":[{"name":"College of Medicine, Chongqing University, Chongqing 400030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Medicine, Chongqing University, Chongqing 400030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weizhe","family":"Yu","sequence":"additional","affiliation":[{"name":"College of Medicine, Xizang University, Lhasa 850000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenxi","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Medicine, Chongqing University, Chongqing 400030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yafang","family":"Pang","sequence":"additional","affiliation":[{"name":"College of Medicine, Chongqing University, Chongqing 400030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Liu","sequence":"additional","affiliation":[{"name":"College of Medicine, Xizang University, Lhasa 850000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayue","family":"Han","sequence":"additional","affiliation":[{"name":"College of Medicine, Chongqing University, Chongqing 400030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youfan","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Medicine, Chongqing University, Chongqing 400030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weizhou","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Medicine, Chongqing University, Chongqing 400030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3134-532X","authenticated-orcid":false,"given":"Shangze","family":"Li","sequence":"additional","affiliation":[{"name":"College of Medicine, Xizang University, Lhasa 850000, China"},{"name":"College of Medicine, Chongqing University, Chongqing 400030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1038\/nri.2016.90","article-title":"Sex differences in immune responses","volume":"16","author":"Klein","year":"2016","journal-title":"Nat. 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