Targeting the STAT3-HIF-1α Signaling Axis Attenuates Isoproterenol-Induced Atrial Fibrosis

<title>Abstract</title> <p>Atrial fibrosis is a major pathological substrate for AF, yet effective targeted therapies remain limited. The STAT3 signaling pathway has been implicated in cardiac remodeling, but its mechanistic interplay with hypoxia-responsive signaling in adrenergic stress-induced atrial fibrosis remains unclear. Here, we investigated the functional relationship between STAT3 and HIF-1α signaling in ISO-induced atrial fibrosis using both a rat model and primary cardiac fibroblasts. Pharmacological interventions included the STAT3 inhibitor S3I-201, the angiotensin-converting enzyme inhibitor enalapril, and the HIF-1α inhibitor 2-ME2. Transcriptomic analysis revealed marked activation of the JAK/STAT pathway, and qPCR confirmed significant STAT3 upregulation during fibrotic remodeling. Inhibition of STAT3 effectively reduced atrial fibrosis, with therapeutic efficacy comparable to enalapril. RNA-seq further suggested that STAT3 inhibition modulates fibrotic remodeling through the HIF-1α pathway. Suppression of HIF-1α attenuated fibrosis and abolished STAT3-driven fibroblast activation, indicating that HIF-1α functions as a critical downstream effector of STAT3. Collectively, our results identify a hierarchical STAT3-HIF-1α signaling axis as an important mediator of ISO-induced atrial fibrosis, providing a mechanistic basis for developing targeted anti-fibrotic strategies in AF.</p>