Beyond a metabolite: lactate and lactylation in lung diseases

Initially regarded as a metabolic byproduct of both anaerobic and aerobic glycolysis, lactate is now recognized as a multifunctional molecule with diverse physiological and pathological roles. Lactate is transported within the body via the lactate shuttle, and acts as a signaling molecule modulating inflammation, angiogenesis, metabolic disorders, fibrosis, cell death and immune dysfunction. The recent discovery of lactylation, revealed that lactate regulates gene transcription and protein function in part by post-translational modification. It is increasingly demonstrated that lactate and lactylation are implicated in a range of pulmonary diseases. Importantly, many pulmonary diseases are associated with a metabolic shift to glycolysis, resulting in lactate overproduction. In this review, we describe lactate metabolism and the discovery of lactylation, and discuss recent findings related to their role in the pathogenesis of lung diseases including acute lung injury, lung fibrosis, pulmonary hypertension, asthma, chronic obstructive pulmonary disease, and lung cancer. Finally, we discuss the therapeutic potential of targeting lactate signaling and lactylation in pulmonary disorders.