Understanding lactate sensing and signalling

•Lactate is a pleiotropic signalling molecule capable of regulating several biological processes, including immune–inflammatory responses, angiogenesis, and fibrosis. •Lactate is sensed via transporters of the families of monocarboxylate transporter (MCT) and sodium monocarboxylate transporter (SMCT) and the G protein-coupled receptors, GPR81 and GPR132. •Lactate is a high-energy carbon molecule actively taken up from the extracellular environment and preferentially used by cells to feed macromolecule biosynthesis. •Lactate carbon-dependent macromolecule biosynthesis is linked to metabolic reprogramming-dependent protein kinase activation and cytokine synthesis. •Lactylation is a newly discovered lactate-dependent post-translational protein modification, and it impacts cell metabolism and function. Metabolites generated from cellular and tissue metabolism have been rediscovered in recent years as signalling molecules. They may act as cofactor of enzymes or be linked to proteins as post-translational modifiers. They also act as ligands for specific receptors, highlighting that their neglected functions have, in fact, a long standing in evolution. Lactate is one such metabolite that has been considered for long time a waste product of metabolism devoid of any biological function. However, in the past 10 years, lactate has gained much attention in several physio-pathological processes. Mechanisms of sensing and signalling have been discovered and implicated in a broad range of diseases, from cancer to inflammation and fibrosis, providing opportunities for novel therapeutic avenues. Here, we review some of the most recently discovered mechanisms of lactate sensing and signalling. Metabolites generated from cellular and tissue metabolism have been rediscovered in recent years as signalling molecules. They may act as cofactor of enzymes or be linked to proteins as post-translational modifiers. They also act as ligands for specific receptors, highlighting that their neglected functions have, in fact, a long standing in evolution. Lactate is one such metabolite that has been considered for long time a waste product of metabolism devoid of any biological function. However, in the past 10 years, lactate has gained much attention in several physio-pathological processes. Mechanisms of sensing and signalling have been discovered and implicated in a broad range of diseases, from cancer to inflammation and fibrosis, providing opportunities for novel therapeutic avenues. Here, we review some of the most recently discovered mechanisms of lactate sensing and signalling.