Sevoflurane alleviates myocardial fibrosis by targeting the YTHDF1/AXL/ferroptosis axis

Background Myocardial fibrosis is a central pathological feature of multiple cardiovascular diseases progressing to heart failure. The molecular mechanisms underlying its development remain incompletely understood, and effective therapeutic targets are lacking. Objective This study aimed to investigate whether sevoflurane alleviates myocardial fibrosis and to elucidate the underlying molecular mechanisms involving the YTHDF1/AXL/ferroptosis axis. Methods A rat model of myocardial fibrosis induced by abdominal aortic constriction (AAC) was established, with groups designated as sham operation (Sham), sevoflurane alone (S), AAC model (AAC), and AAC + sevoflurane (AAC + S). The degree of fibrosis was evaluated by Masson staining and immunohistochemistry. In vitro, human atrial fibroblasts (HAFs) were induced to undergo fibrosis by angiotensin II (Ang-II). Combined with sevoflurane intervention, ferroptosis inhibitor (Fer-1) treatment, YTHDF1 overexpression/knockdown, and PI3K inhibitor treatment, Western blot, qPCR, and detection of ferroptosis indicators (e.g., Fe 2+ , MDA) were used to analyze the related regulatory mechanisms. Results In vivo experiments showed that sevoflurane significantly reduced cardiomyocyte surface area, left ventricular collagen volume fraction, and the expression of type I/III collagen in AAC rats, thereby improving myocardial fibrosis. In vitro, sevoflurane promoted ferroptosis in Ang-II-induced HAFs, as evidenced by increased levels of Fe 2+ , MDA, and ROS; decreased activities of SOD, GSH, and GSH-Px; downregulated expression of GPX4 and SLC7A11; and upregulated expression of NCOA4. Meanwhile, sevoflurane inhibited the expression of fibrosis-related proteins (α-SMA, Collagen I, Collagen III). Blocking ferroptosis (via Fer-1 intervention) attenuated the anti-fibrotic effect of sevoflurane. Mechanistically, sevoflurane downregulated the expression of YTHDF1 and AXL and inhibited the activation of the PI3K/AKT signaling pathway. Overexpression of YTHDF1 reversed sevoflurane-induced ferroptosis and its anti-fibrotic effect. YTHDF1/AXL regulated fibrosis by activating the PI3K/AKT pathway, and this effect could be blocked by a PI3K inhibitor. Conclusion Sevoflurane attenuates myocardial fibrosis by downregulating the YTHDF1/AXL axis, suppressing PI3K/AKT signaling, and inducing ferroptosis in cardiac fibroblasts, providing novel therapeutic targets for myocardial fibrosis.