Can ketones explain the immune benefits of time-restricted eating? Time-restricted eating (TRE) has become one of the most widely adopted dietary interventions for metabolic health. Yet a fundamental question remains unanswered: Are the anti-inflammatory effects of TRE driven by meal timing itself—or by fasting-induced ketone metabolism? A new narrative review in Metabolism synthesizes current human evidence linking TRE, immunomodulation, and ketone biology, highlighting both promising findings and major mechanistic gaps. The overall picture is encouraging but far from definitive. Across human studies, TRE is associated with modest reductions in inflammatory biomarkers including TNF-α, CRP, IL-6, leptin, and increases in adiponectin. However, results vary considerably between studies, with nearly half reporting no significant changes. Importantly, many positive findings occurred alongside weight loss and caloric restriction, making it difficult to determine whether TRE itself is responsible. Ketone metabolism offers an intriguing mechanistic explanation. Extending the fasting period should theoretically increase hepatic ketogenesis and circulating β-hydroxybutyrate (BHB). Yet surprisingly, only a handful of human TRE studies have actually measured ketones, and most observed only small or transient increases that remained well below nutritional ketosis. Evidence from longer fasting paradigms strengthens the hypothesis. Alternate-day fasting and prolonged fasting consistently elevate ketone bodies while improving inflammatory diseases, suggesting that fasting duration may determine whether meaningful ketogenesis occurs. Mechanistically, BHB is far more than an alternative fuel. The review highlights two complementary pathways: • Metabolic signaling: BHB enhances oxidative phosphorylation, supports TCA-cycle metabolism, and improves CD4⁺ and CD8⁺ T-cell function. • Non-metabolic signaling: BHB suppresses the NLRP3 inflammasome, inhibits HDAC activity, activates GPR109A signaling, promotes β-hydroxybutyrylation, and ultimately reduces production of pro-inflammatory cytokines including IL-6, TNF-α and CRP. However, the key limitation is striking: No human TRE study has directly demonstrated that TRE-induced ketone production mediates immune modulation. Current evidence is therefore mechanistic and inferential rather than causal. The review also emphasizes an important experimental challenge. Most TRE trials unintentionally reduce calorie intake and body weight. Because weight loss itself lowers inflammation, separating meal timing, energy restriction, and ketone signaling remains difficult. Carefully controlled isocaloric TRE studies will be required to identify the true biological driver. Several important knowledge gaps remain: • Does early TRE produce more ketones than late TRE? • What fasting duration is necessary to generate biologically meaningful BHB? • Are ketones responsible for immune remodeling or simply biomarkers of fasting? • Can ketone flux—not just circulating concentration—predict immunometabolic benefits? The take-home message is nuanced. TRE consistently appears safe and metabolically beneficial, but the ketone–immune axis remains one of the largest unanswered questions in chrononutrition. Resolving this question may help explain how a simple behavioral intervention could influence chronic inflammatory, metabolic, cardiovascular, and autoimmune diseases. Reference Macheret NA, Thota GP, Hengist A, et al. Time-restricted eating, immunomodulation and ketone metabolism in humans. Metabolism (2026). DOI: doi.org/10.1016/j.metabol.20…