ECM stiffness inhibits ferroptosis to promote HCC progression via the FOXA1-CDON-HMGB1/p53 pathway.

The progression of hepatocellular carcinoma (HCC) is closely associated with the physical microenvironment, particularly the stiffness of the extracellular matrix (ECM). However, the molecular mechanisms by which the ECM influences HCC progression remain unclear. We demonstrate that a stiff ECM promotes HCC progression and identify the key regulatory molecule CDON using a polyacrylamide hydrogel model, transcriptome sequencing, and other assays. A gradual increase in ECM stiffness upregulates CDON expression, and elevated CDON levels are associated with poor prognosis. CDON is highly expressed in HCC cells and tissues, where it enhances invasion, metastasis, and proliferation. ECM stiffness regulates HCC progression through CDON. In the cytoplasm, CDON binds to HMGB1, reducing HMGB1 levels in both the cytoplasm and nucleus. This reduction leads to the release of p53 from the nucleus into the cytoplasm and its degradation through the ubiquitination-proteasome pathway, weakening p53's transcriptional repression of SLC7A11 and thereby inhibiting ferroptosis, which promotes sorafenib chemotherapy resistance in HCC cells. Additionally, stiff ECM promotes the nuclear translocation of YAP1 via integrins. Once in the nucleus, YAP1 binds to the transcription factor FOXA1 to regulate CDON transcription. This study demonstrates that stiff ECM serves as an indicator for differentiating HCC progression and chemotherapy resistance. Targeting the "CDON-ferroptosis" axis may offer a novel combined treatment strategy.