SPARC boost cholesterol-dependent aggressive phenotype and sorafenib resistance in hepatocellular carcinoma

Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, is characterized as a highly aggressive tumor entity and has become a health challenge worldwide. Intracellular secreted protein acidic and rich in cysteine (SPARC) has been described as secreted protein that serves as paracrine mediator between cells extracellular matrix (ECM), however, its intracellular role remains unclear. Genetically modified HCC cell lines, cancer patient-derived organoids, and mouse models were used to analyze SPARC on metabolic processes, as well as the invasive behavior and sorafenib resistance of HCC cells. Transcriptome, interactome, and biochemical analyses were performed to study how SPARC regulate cholesterol homeostasis. High expression of intracellular SPARC was significantly associated with elevated cholesterol levels and an enhanced invasive phenotype in HCC. Our findings unveil a previously unrecognized interplay between SPARC and cholesterol homeostasis. Targeting SPARC-triggered cholesterol-dependent oncogenic signaling serves as a promising strategy for treating advanced HCC.