Lactylation: a promising target for musculoskeletal disorders via interactions with chronic inflammation.

Musculoskeletal disorders (MSDs) encompass conditions that affect bones, joints, and muscles, leading to substantial pain and functional impairment and representing a major global health concern. In MSDs, key metabolic processes-such as glycolysis and lactate accumulation under hypoxic conditions-disrupt cellular energy homeostasis. Lactylation, a post-translational modification arising from excessive lactate, modifies both histone and non-histone proteins and has been implicated in inflammation and MSD pathogenesis. Preclinical studies indicate that targeting lactylation holds promise for the treatment of various MSDs. Systemic, chronic, low-grade inflammation (SCLGI) is thought to contribute to both the onset and persistence of many MSDs, with its unresolved state driving chronic disease progression. Promoting the resolution of SCLGI may alleviate symptoms, particularly through specialized pro-resolving mediators (SPMs) derived from dietary essential polyunsaturated fatty acids (PUFAs). Both SPMs and their small-molecule analogs have demonstrated therapeutic benefits in animal models of inflammation-related disorders, including arthropathies, osteoporosis, and muscular dystrophy. This review proposes a novel therapeutic strategy for MSDs that integrates lactylation inhibitors or agonists with agents that facilitate SCLGI resolution. Such a combined approach may enhance the effectiveness of MSD management.