FXYD3 Promotes Tumor Progression by Binding With IRF7 to Regulate JAK2/STAT5 Signaling in Intrahepatic Cholangiocarcinoma

Abstract Intrahepatic cholangiocarcinoma (ICC) has a poor prognosis, especially for inoperable patients. FXYD3, an FXYD‐domain‐containing regulator in the Na+/K+ ATPase family, is overexpressed in several common cancers. However, its role in ICC progression remains unclear. We integrated multiple ICC single‐cell transcriptome profiles from publicly available datasets and analyzed them using various bioinformatic methods, identifying FXYD3 as a candidate gene. In vitro and in vivo experiments demonstrated that FXYD3 expression was upregulated in ICC tumor tissues and associated with tumor progression and unfavorable prognosis. Subsequently, a combination of single‐cell sequencing, high‐resolution spatial transcriptome analysis, and a series of experimental assays demonstrated that FXYD3 directly interacts with IRF7 via its 60‐87aa domain, thereby initiating a positive feedback loop mediated by the cGAS/STING pathway. This loop is amplified by interferon type I and results in sustained activation of the JAK2/STAT5 signaling pathway, ultimately driving the malignant progression of ICC. The targeted FXYD3 nano‐delivery system (siFXYD3@PEP) exhibited significant antitumor efficacy in spontaneous and transplanted tumor models and markedly enhanced the sensitivity of ICC to standard gemcitabine and cisplatin chemotherapy. Our findings highlight the role of FXYD3 in cancer‐related inflammation and innate immune signaling, thereby providing a new paradigm for understanding the pathogenesis of ICC.