Objective:

To explore the biological mechanisms underlying the antidepressant effects of exercise, focusing on the lactate-HCAR1 pathway and its potential connection to inflammation-related depression.

Approach:

• Review of Mechanisms: The review discusses conventional brain-centered mechanisms of exercise-induced antidepressant effects, including BDNF signaling and monoaminergic modulation, and introduces the lactate-HCAR1 axis as a potential link to inflammation-related depression.

Key Findings:

• Exercise-induced lactate acts as a dynamic immunometabolic signal rather than merely a metabolic byproduct.
• The lactate-HCAR1 pathway may connect exercise metabolism to immune regulation and inflammation-related depressive symptoms, though evidence supporting its components varies.

Interpretation:

The review frames lactate-informed exercise prescription as a testable hypothesis, suggesting future studies should investigate various biological responses to exercise in depression.

Limitations:

• Some components of the lactate-HCAR1 pathway are inferential and require validation.
• The framework does not establish definitive biomarker-defined subtypes of depression.

Conclusion:

If validated, the proposed framework may help identify which patients benefit from exercise and how exercise can be studied as an immunometabolic intervention.