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Differential bioenergetic reprogramming driven by sorafenib reveals therapeutic vulnerabilities in biliary tract cancers

ABSTRACT: Biliary tract cancers (BTCs) comprise biologically heterogeneous subtypes with limited therapeutic options and variable responses to sorafenib. The biological basis underlying this variability remains unclear. In this study, we compared intrahepatic cholangiocarcinoma (iCCA) and gallbladder cancer (GBC) models under defined sorafenib exposure conditions using transcriptomic profiling, Seahorse-based mitochondrial stress assays, pharmacologic combination analysis, and patient-derived organoid models. In representative iCCA models, 1.25 μM sorafenib increased mitochondrial respiration and ATP production, whereas 10 μM sorafenib suppressed this respiratory adaptation. In contrast, representative GBC models exhibited persistent suppression of mitochondrial respiratory function across the tested conditions and did not display a comparable concentration-dependent shift. Integrated transcriptomic and pharmacologic analyses further identified mitochondrial Complex I as a treatment-relevant vulnerability under sorafenib exposure, with stronger combination interactions observed in iCCA models. These findings indicate that iCCA and GBC differ in their metabolic responses to sorafenib and highlight subtype-specific differences in mitochondrial adaptation under treatment stress.

ORGANISM(S): Homo sapiens

PROVIDER: GSE343131 | GEO | 2026/08/15

REPOSITORIES: GEO

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Project description:Background: Sorafenib, a multi-kinase inhibitor widely used in hepatocellular carcinoma, is associated with clinically relevant cardiotoxicity, but the underlying mechanisms remain incompletely understood. Cardiac macrophages are key regulators of inflammatory injury in the heart; however, their role in sorafenib-induced cardiotoxicity (SIC) has not been fully defined. Methods: A murine model of SIC was established in C57BL/6J mice. Indirect macrophage-cardiomyocyte co-culture systems were used for in vitro mechanistic studies. Macrophages were depleted in vivo using PLX3397. Transcriptomic profiling was performed to identify candidate mediators associated with macrophage-related SIC. PDE2A was further investigated using genetic knockdown and pharmacological inhibition in cellular and animal models. Results: Sorafenib induced cardiac dysfunction, myocardial injury, and inflammatory remodeling in vivo, accompanied by increased cardiac macrophage infiltration and a shift toward a pro-inflammatory phenotype. In vitro, macrophages exacerbated sorafenib-induced cardiomyocyte injury, oxidative stress, and mitochondrial dysfunction, whereas macrophage depletion attenuated SIC in vivo. Transcriptomic analysis identified PDE2A as an upregulated candidate in sorafenib-injured hearts, and this increase was reduced by macrophage depletion. PDE2A expression was preferentially increased in macrophages rather than cardiomyocytes under sorafenib exposure. Genetic or pharmacological inhibition of PDE2A attenuated injury-related phenotypes and inflammatory activation in vitro and alleviated SIC in vivo. Mechanistically, these effects were predominantly associated with cGMP/PKG signaling rather than cAMP/PKA signaling. In tumor-bearing models, BAY60-7550 did not compromise the anti-tumor effect of sorafenib and was associated with enhanced tumor suppression. Conclusion: These findings indicate that sorafenib-induced cardiotoxicity is closely associated with macrophage-driven inflammatory remodeling and identify PDE2A as a candidate mediator of this process. Pharmacological inhibition of PDE2A attenuated cardiac injury while maintaining, and potentially enhancing, the anti-tumor activity of sorafenib, supporting PDE2A as a potential therapeutic target in this setting.

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Differential bioenergetic reprogramming driven by sorafenib reveals therapeutic vulnerabilities in biliary tract cancers

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