Ketone body metabolism has gained increasing attention as a key regulator of immunometabolic homeostasis. Beyond serving as alternative energy substrates during fasting or ketogenic states, ketone bodies—particularly β-hydroxybutyrate—function as signaling molecules capable of modulating inflammation and immune responses. Emerging evidence suggests that ketone body–mediated immunoregulation may have significant therapeutic implications for autoimmune and inflammatory disorders. However, the underlying mechanisms and translational potential of targeting ketone body metabolism have not yet been comprehensively summarized. This review provides an integrated overview of the molecular and cellular mechanisms through which ketone bodies influence immune function. We discuss how β-hydroxybutyrate regulates macrophages and T cells via inhibition of the NOD-like receptor pyrin domain–containing 3 (NLRP3) inflammasome, activation of hydroxycarboxylic acid receptor 2 (HCAR2), and epigenetic reprogramming including histone β-hydroxybutyrylation. Furthermore, we examine current strategies for modulating ketone body metabolism, including the ketogenic diet, exogenous ketone supplementation, sodium–glucose cotransporter 2 inhibitors, and metabolic enzyme regulators. Preclinical studies and early clinical evidence indicate potential anti-inflammatory and immunomodulatory benefits of these interventions in diseases such as multiple sclerosis, inflammatory bowel disease, gout, metabolic dysfunction–associated steatohepatitis, and atherosclerosis. Collectively, current findings support ketone body metabolism as a promising therapeutic target within the field of immunometabolism. Modulation of ketone body pathways may offer novel strategies for controlling chronic inflammation and autoimmune pathology. Future studies are required to optimize intervention protocols, clarify long-term safety, and bridge the gap between basic mechanistic research and clinical translation.
Gong et al. (Wed,) studied this question.