Metabolic Dysregulation-driven Protein Acylation in Osteoarthritis
- VernacularTitle:骨关节炎中代谢异常驱动的酰化修饰调控
- Author:
Zi-Hao ZHANG
1
;
Li DUAN
1
;
Kan OUYANG
2
;
Tayyab SHAFIQ
3
Author Information
- Publication Type:Journal Article
- Keywords: osteoarthritis; metabolic abnormalities; acylation modification; acetylation; lactylation; SIRT5
- From: Progress in Biochemistry and Biophysics 2026;53(10):2703-2713
- CountryChina
- Language:Chinese
- Abstract: Osteoarthritis (OA) is a common chronic degenerative joint disease and a major cause of pain and disability, particularly in middle-aged and older adults. OA is now recognized as a whole-joint disorder involving articular cartilage, synovium, subchondral bone, the meniscus, the infrapatellar fat pad, and the local inflammatory microenvironment. In addition to mechanical factors, metabolic abnormalities such as obesity, dyslipidemia, insulin resistance, and hyperglycemia are increasingly recognized as contributors to OA onset and progression. Obesity can increase mechanical joint loading, whereas metabolic abnormalities alter cellular metabolism and inflammatory responses within joint tissues. However, the molecular mechanisms by which metabolic stress leads to persistent cellular dysfunction and tissue damage remain incompletely understood. Protein acylation links cellular metabolism to chromatin regulation and protein function. Its dynamic balance is influenced by acyl-donor availability, cellular redox status, mitochondrial activity, glycolytic flux, and the activities of acyltransferases and deacylases. In OA, mitochondrial dysfunction, enhanced glycolysis, lactate accumulation, altered acyl-CoA metabolism, and dysregulated NAD+-dependent deacylation may reshape histone and non-histone protein acylation. These changes have been implicated in inflammatory gene expression, extracellular matrix metabolism, mitochondrial quality control, chondrocyte senescence, ferroptosis susceptibility, and synovial immune dysfunction. Recent studies increasingly focus on defined acylation sites, target proteins, regulatory enzymes, and cell-type-specific effects. Acetylation and deacetylation are involved in OA-related processes. sirtuin 1 (SIRT1)-mediated regulation of nuclear factor kappa-B (NF-κB) p65 acetylation is associated with inflammatory and catabolic responses, whereas histone deacetylase 3 (HDAC3)-dependent control of Parkin acetylation links matrix stiffening to excessive mitophagy and chondrocyte senescence. SIRT3-related pathways connect nicotinamide adenine dinucleotide (NAD+)-dependent deacetylation with mitochondrial DNA integrity, mitochondrial renewal, and metabolic remodeling, while SIRT6 has been implicated in inflammation and cellular senescence. Lactylation has emerged as another important direction in OA research. Histone H3 lysine 18 (H3K18) lactylation is associated with glycolysis-related transcription through the lactate dehydrogenase A (LDHA)-H3K18la-triosephosphate isomerase 1 (TPI1) axis. UGDH K6 lactylation impairs glycosaminoglycan synthesis and promotes matrix damage, whereas H4K12 lactylation has been linked to chondrocyte senescence and autophagy inhibition. In the synovial microenvironment, cluster of differentiation 11b (CD11b) lactylation in macrophages impairs efferocytosis and contributes to sustained inflammation under hyperglycemic conditions. In contrast, H3K56 lactylation has been associated with increased type II collagen synthesis in a post-traumatic OA model, indicating that lactylation effects depend on the modified site, target, cell state, and disease context. SIRT5-related malonylation and succinylation provide additional links between acylation and metabolic dysfunction in OA. Increased protein malonylation and reduced SIRT5 activity are associated with disturbed glycolysis, mitochondrial respiration, and carbon metabolism in chondrocytes. SIRT5-mediated acyl-CoA synthetase long-chain family member 4 (ACSL4) desuccinylation has been linked to reduced lipid peroxidation and ferroptosis susceptibility. By contrast, OA-specific evidence for crotonylation remains limited and centers on crotonylation-related metabolic genes such as glutaryl-CoA dehydrogenase (GCDH) rather than defined functional acylation sites. This review summarizes current evidence linking metabolic dysregulation to acylation regulation in OA. Collectively, available studies indicate that shared metabolic disturbances reshape distinct acylation programs across joint cell types, producing modification- and site-specific effects on cellular function and tissue homeostasis. However, evidence strength varies among acylation types, particularly regarding defined functional sites and in vivo causality. Further site-specific and in vivo studies are needed to clarify which acylation changes actively contribute to OA progression and to evaluate their mechanistic and therapeutic relevance.
