The lactate-HCAR1 axis in exercise psychiatry: a candidate mechanism linking bone marrow-brain immunity to...

Exercise is increasingly acknowledged as an effective intervention for depression, yet the biological mechanisms underlying its antidepressant effects remain incompletely defined. Conventional models have emphasized brain-centered pathways, including BDNF signaling, monoaminergic modulation, hypothalamic-pituitary-adrenal axis regulation, hippocampal neurogenesis, and synaptic plasticity. These mechanisms are important, but they may not fully explain depression phenotypes characterized by elevated inflammatory burden, fatigue, anhedonia, diminished motivation, psychomotor slowing, cognitive inefficiency, and altered peripheral immune activity. This review proposes that exercise-induced lactate should be considered not only as a metabolic substrate or byproduct, but also as a dynamic immunometabolic signal. Appropriately dosed exercise can generate a transient and recoverable lactate pulse that may be detected by immune, vascular, and brain-associated cells through hydroxycarboxylic acid receptor 1, also known as HCAR1 or GPR81. We propose that the lactate-HCAR1 axis could represent a candidate mechanism linking exercise metabolism to bone marrow myeloid regulation, peripheral inflammatory tone, brain vascular and border interfaces, glial responses, and inflammation-related depressive symptom dimensions. The framework integrates skeletal muscle metabolism, myelopoiesis, peripheral myeloid cells, blood-brain interfaces, microglia, astrocytes, and endothelial cells into a cross-organ model of exercise psychiatry. Importantly, the strength of evidence differs across this pathway: some components are supported by human exercise physiology or preclinical causal studies, whereas others remain inferential and require validation in patients with depression. We therefore frame lactate-informed exercise prescription as a testable translational hypothesis rather than a clinically established strategy. Future studies should examine lactate kinetics, inflammatory biomarkers, immune cell phenotypes, symptom dimensions, safety, recovery dynamics, and comparisons with conventional heart-rate-, VO₂-, or perceived-exertion-based prescriptions. If validated, this framework may help identify which patients benefit from exercise, which biological responses are meaningful, and how exercise can be studied as a quantifiable immunometabolic intervention.