Targeting ferritinophagy via NCOA4-FTH1 disruption by sodium tanshinone IIA sulfonate alleviates cardiotoxicity and enhances anti-tumor efficacy.

Background

Sorafenib remains a first-line therapy for advanced hepatocellular carcinoma (HCC), yet its clinical utility is frequently limited by dose-dependent cardiotoxicity for which no targeted intervention exists. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has been implicated as a key mechanism underlying chemotherapy-induced cardiac injury. However, existing ferroptosis inhibitors lack tissue selectivity and may attenuate the anti-tumor efficacy of sorafenib, creating an unresolvable therapeutic conflict.

Objective

This study aimed to identify a pharmacological agent that simultaneously mitigates sorafenib-induced cardiotoxicity and potentiates its anti-tumor activity through selective modulation of ferroptosis.

Methods

We integrated computational structural prediction, surface plasmon resonance (SPR), and cellular thermal shift assay (CETSA) to identify and validate direct protein-small-molecule interactions. Functional characterization was performed using AC16 cardiomyocytes and multiple HCC cell lines, with assessments of cell viability, labile iron pools, lipid reactive oxygen species, malondialdehyde content, and mitochondrial function. The in vivo therapeutic efficacy was evaluated in a sorafenib-induced cardiac injury mouse model, accompanied by quantitative proteomics to delineate the molecular pathways modulated by sodium tanshinone IIA sulfonate (STS).

Results

STS was identified as a direct modulator of the NCOA4-FTH1 interaction, selectively disrupting ferritinophagy at the cargo-recognition stage and thereby limiting iron release, oxidative stress, and downstream lipid peroxidation. SPR confirmed a direct STS-FTH1 binding affinity (KD=2.19 μM), and CETSA validated target engagement in intact cells. In vivo, STS markedly attenuated sorafenib-induced cardiac injury, restoring antioxidant capacity and mitochondrial function. Quantitative proteomics demonstrated that STS reversed sorafenib-driven disruption of oxidative stress pathways. Notably, STS simultaneously potentiated sorafenib cytotoxicity across multiple cancer cell lines, significantly reducing IC₅₀ values-an effect attributable to the divergent iron metabolic states between tumor cells and cardiomyocytes.

Conclusion

Our findings establish ferritinophagy as a therapeutically tractable upstream regulator of ferroptosis and identify STS as a dual-functional agent that both alleviates sorafenib-induced cardiotoxicity and enhances its anti-tumor efficacy. This study provides a mechanistic framework for improving the therapeutic index of sorafenib and highlights cargo-recognition targeting as a promising strategy for tissue-selective ferroptosis modulation.