Background: Multiple oral insulin-sensitizing agents, such as metformin, thiazolidinediones, inositols, and berberine, have been proven safe and efficacious in improving the endocrine, metabolic, and reproductive abnormalities seen in polycystic ovary syndrome (PCOS), providing more options for healthcare providers and patients. These oral insulin sensitizers are more convenient, practical, and economic than agents that need to be injected. A comparison of the clinical effectiveness of the four different classes of oral insulin sensitizers in PCOS has not been explored, leading to clinical uncertainty about the optimal treatment pathway. The present study aims to compare the effects of oral insulin sensitizers on endocrine and metabolic profiles in women with PCOS.Methods: We identified randomized controlled trials for PCOS from a variety of databases, published from January 2005 to October 2020. Outcomes included changes in menstrual frequency, improvements in hyperandrogenism and glucolipid metabolism and adverse side effects. A random-effects network meta-analysis was performed.Results: Twenty-two trials comprising 1079 patients with PCOS were included in this study. Compared with metformin, treatment with myo-inositol + d-chiro-inositol was associated with a greater improvement in menstrual frequency (odds ratio 14.70 [95% confidence interval (CI) 2.31–93.58]). Myo-inositol + d-chiro-inositol and metformin + thiazolidinediones combination therapies were superior to respective monotherapies in reducing total testosterone levels. Thiazolidinediones, metformin + thiazolidinediones, and myo-inositol + d-chiro-inositol were associated with a lower insulin resistance index (HOMA-IR) compared with that in metformin alone (mean differences: − 0.72 [95% CI (− 1.11)–(− 0.34)] to − 0.89 [95% CI (− 1.460)–(− 0.32)]). Metformin + thiazolidinediones treatment was associated with lower triglyceride levels compared with that in metformin and thiazolidinediones monotherapy, while thiazolidinediones was superior to metformin in increasing high-density lipoprotein cholesterol and decreasing fasting plasma glucose, triglycerides, low-density lipoprotein cholesterol, and gastrointestinal adverse events.Conclusions: Ours is the first study to report that for women with PCOS, myo-inositol combined withd-chiro-inositol and metformin combined with thiazolidinediones appear superior to metformin alone in improving insulin resistance and decreasing total testosterone. Myo-inositol combined withd-chiro-inositol is particularly efficacious in menstrual recovery. Thiazolidinediones and metformin combined with thiazolidinediones improve lipid metabolism better than metformin alone.Trial registrationPROSPERO CRD42020211524

Synovial hyperplasia is a hallmark of rheumatoid arthritis (RA), yet its mechanism remains unclear. RA synovium exhibits metabolic shift, characterized by upregulated glycolysis and enhanced lactate production. In this study, we elucidated the mechanism underlying the roles of lactate metabolism and protein lactylation in RA pathology. In patients with RA, both lactate production and protein lactylation were elevated and showed a positive correlation with clinical disease activity. These changes were further implicated in driving synovial proliferation. Among the lactylated proteins, Cysteine-rich intestinal protein 1 (CRIP1) exhibited a marked increase in modification and played a central role in promoting synovial proliferation. Mechanistically, CRIP1 underwent MOF-mediated lactylation in RA synovial fibroblasts. Lactylated CRIP1 hijacked the cell-cycle regulator p21, disrupting its interaction with cyclin-dependent kinase 2 (CDK2), thereby facilitating the G1/S phase transition. Functionally, AAV-mediated delivery of a lactylation-deficient CRIP1 K49R significantly reduced synovial proliferation compared with WT CRIP1. Peptide-based interventions targeting CRIP1 K49 lactylation effectively inhibited synovial hyperplasia and disease severity in both Collagen II–induced arthritis (CIA) and humanized NSG chimeric models. Collectively, CRIP1 protein lactylation drives synovial proliferation in RA by hijacking p21 from CDK2, thereby facilitating cell cycle progression. Targeting this pathway may serve as a promising strategy for RA.