Background Rhabdomyolysis (RM) is a common complication of exertional heat stroke (EHS) and constitutes a direct cause of death. However, the mechanism underlying RM following EHS remains unclear. Methods The murine EHS model was prepared by our previous protocol. RNA sequencing is applied to identify the pathological pathways that contribute to RM following EHS. Inhibition of the acyl‐CoA synthetase long‐chain family member 4 (ACSL4) was achieved by RNA silencing in vitro prior to ionomycin plus heat stress exposure or pharmacological inhibitors in vivo prior to heat and exertion exposure. The histological changes, the iron accumulation, oxidized phosphatidylethanolamines species, as well as histological evaluation and levels of lipid metabolites in skeletal muscle tissues were measured. Results We demonstrated that ferroptosis contributes to RM development following EHS. Ferroptosis inhibitor ferrostatin‐1 administration once EHS onset significantly ameliorated the survival rate of EHS mice from 35.357% to 52.288% within 24 h after EHS (P = 0.0028 compared with control) and markedly inhibited RM development induced by EHS. By comparing gene expression of between sham heat rest (SHR) (n = 3) and EHS (n = 3) mice in the gastrocnemius (Gas) muscle tissue, we identified that Acsl4 mRNA expression is elevated in Gas muscle tissue of EHS mice (P = 0.0038 compared with SHR), so as to its protein levels (P = 0.0001 compared with SHR). Followed by increase in creatine kinase (CK) and myoglobin (MB) levels, the labile iron accumulation, decrease in glutathione peroxidase 4 (GPX4) expression, and elevation of lipid peroxidation products. From in vivo and in vitro experiments, inhibition of Acsl4 significantly improves muscle cell death caused by EHS, thereby ameliorating RM development, followed by reduction in CK and MB levels by 30–40% (P < 0.0001; n = 8–10) and 40% (P < 0.0001; n = 8–10), restoration of GPX4 expression, and decrease in lipid peroxidation products. Mechanistically, ACSL4‐mediated RM seems to be Yes‐associated protein (YAP) dependent via TEA domain transcription factor1/TEA domain transcription factor4. Conclusions These findings demonstrate an important role of ACSL4 in mediating ferroptosis activation in the development of RM following EHS and suggest that targeting ACSL4 may represent a novel therapeutic strategy to limit the skeletal muscle cell death and prevent RM after EHS.

Osteoarthritis (OA) imposes an increasing social burden due to global activity limitations, especially among the aged. Links between circulating lipids and OA have been reported; however, confounding data from observational studies have hindered causal conclusions. We used Mendelian randomization (MR) approach to evaluate the genetic causal effects of circulating apolipoproteins and lipoprotein lipids on OA risk. Genetic instruments at the genome-wide significance level (p < 5 × 10−8) were selected from genome-wide association studies (n = 393,193–441,016 individuals). Summary-level OA data were obtained from the UK Biobank (39,427 cases, 378,169 controls). Bidirectional two-sample Mendelian randomization (MR) analyses used MR-Egger, weighted median, and MR-PRESSO for sensitivity analysis. Genetic predisposition to 1-SD increments of Apolipoprotein B (APOB), and low-density lipoprotein (LDL) was associated with a decreased risk of knee or hip OA (KHOA) (odds ratio (OR) = 0.925, 95% confidence interval (95% CI): 0.881–0.972, p = 0.002; OR = 0.898, 95% CI: 0.843–0.957, p = 0.001) and hip OA (HOA) (OR = 0.894; 95% CI: 0.832–0.961, p = 0.002; OR = 0.870 95% CI: 0.797–0.949, p = 0.002). Genetically predicted APOB showed an association with knee OA (KOA) (OR per SD increase, 0.930, 95% CI: 0.876–0.987, p = 0.016). The OR of KOA was 0.899 (95% CI: 0.835–0.968, p = 0.005) for a 1-SD increase in LDL. Apolipoprotein A1, high-density lipoprotein, and triglycerides showed no association. Inverse MR showed no causal effect of KOA, HOA, or KHOA on these serum lipids. Distinct protective genetic-influence patterns were observed for APOB and LDL on OA, offering new insights into relationships between lipids and OA risk and a better understanding of OA etiology.

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Ovarian cancer (OC), and particularly epithelial OC (EOC), is an increasing challenge for women. Circulating lipids play different roles in the occurrence and development of OC, but no causal relationship has been confirmed. We used two-sample Mendelian randomization (MR) to evaluate the genetic effects of circulating Apolipoprotein A1 (APOA1), Apolipoprotein B (APOB), high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyc-erides (TG) on EOC risks based on summary data obtained from the UK Biobank and the Ovarian Cancer Association Consortium. We used the inverse-variance weight as the main statistical method and the MR-Egger, weighted median, and MR-PRESSO for sensitivity analysis. A 1-SD increment in HDL gave odds ratios (OR) and 95% confidence intervals (CI) of OR = 0.80 (95% CI: 0.69–0.93), OR = 0.77 (95% CI: 0.66–0.90), and OR = 0.76 (95% CI: 0.63–0.90) for low malignant potential OC (LMPOC), low-grade low malignant OC (LGLMSOC), and low malignant serous OC (LMSOC), respectively. Genetic liability due to TG was associated with an increased risk of LGLMSOC and LGSOC and a suggestive association with an increased risk of LMSOC (p = 0.001, p = 0.007, and p = 0.027, respectively). Circulating HDL was negatively associated with the risk of LMPOC, LGLMSOC, and LMSOC, while elevated circulating TG levels genetically predicted an increased risk of LGLMSOC and LGSOC. Further research is needed to investigate the causal effects of lipids on EOC and potential intervention and therapeutic targets.