{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T18:58:28Z","timestamp":1787770708117,"version":"build-2784847793"},"reference-count":169,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T00:00:00Z","timestamp":1776816000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Branched-chain amino acids (BCAAs)\u2014leucine, isoleucine, and valine\u2014are essential nutrients that exhibit context-dependent, paradoxical effects on human health, with mTORC1 (mechanistic target of rapamycin complex 1) signaling serving as a central mechanistic node through which physiological BCAA concentrations support anabolism and repair while chronic pathological elevation drives metabolic and inflammatory injury. While their anabolic properties in promoting muscle protein synthesis, modulating immune responses, and conferring hepatoprotection are well-documented, accumulating evidence demonstrates that chronically elevated circulating BCAA concentrations are strongly associated with the pathogenesis and progression of metabolic, inflammatory, and injury-related diseases, including insulin resistance, type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD), metabolic dysfunction-associated steatotic liver disease (MASLD, formerly NAFLD), and certain malignancies. This biological duality is mechanistically rooted in a network of interconnected pathological processes, in which BCAA-mediated modulation of mTORC1 signaling\u2014already introduced above\u2014represents one central hub operating alongside impaired catabolic flux, accumulation of branched-chain \u03b1-keto acids (BCKAs) and branched-chain acylcarnitines, mitochondrial redox imbalance, and cellular stress pathway activation. Physiological BCAA concentrations support anabolic processes and cellular repair, whereas chronic pathological elevation is associated with mTORC1 hyperactivation alongside impaired BCKDH-mediated catabolic flux, accumulation of branched-chain \u03b1-keto acids (BCKAs) and branched-chain acylcarnitines, mitochondrial redox imbalance, and activation of cellular stress pathways\u2014collectively contributing to disrupted metabolic homeostasis, amplified inflammatory cascades, and mitochondrial dysfunction. The ultimate biological impact of BCAAs is not intrinsic to these amino acids but rather is determined by a complex interplay of factors including: dosage and duration of exposure, individual metabolic status (particularly insulin sensitivity and mitochondrial oxidative capacity), specific disease context, and genetic polymorphisms affecting BCAA metabolism alongside gut microbiome composition. This review comprehensively synthesizes current understanding of BCAA biology and advocates for a paradigm shift toward precision nutrition approaches. Evidence supports therapeutic BCAA supplementation in hypercatabolic conditions such as sarcopenia and hepatic cirrhosis, while suggesting potential adverse metabolic consequences in insulin-resistant or obese individuals. Future nutritional and therapeutic strategies should transition from universal dietary recommendations to personalized interventions based on comprehensive metabolic phenotyping and genetic profiling, thereby optimizing BCAA intake for individual health trajectories and providing novel preventive and therapeutic opportunities for chronic disease management.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1778455","type":"journal-article","created":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T05:51:29Z","timestamp":1776837089000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Angel or demon? The dual role of branched-chain amino acids in chronic inflammatory and injury-related diseases"],"prefix":"10.3389","volume":"17","author":[{"given":"Jiaxin","family":"Li","sequence":"first","affiliation":[{"name":"Liaoning University of Traditional Chinese Medicine","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hurong","family":"Chen","sequence":"additional","affiliation":[{"name":"Liaoning University of Traditional Chinese Medicine","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Zhou","sequence":"additional","affiliation":[{"name":"Liaoning University of Traditional Chinese Medicine","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liya","family":"Sun","sequence":"additional","affiliation":[{"name":"Liaoning University of Traditional Chinese Medicine","place":["Shenyang, 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