CD47-SIRPα axis mediated by ncRNA correlates with poor prognosis, immune microenvironment dysregulation and lipid metabolism modulation in hepatocellular carcinoma.

The cluster of differentiation 47 (CD47)-signal regulatory protein α (SIRPα) axis plays crucial roles in tumour immune evasion, promoting tumorigenesis and malignancy progression. Preclinical studies have demonstrated that CD47 blockade synergises with anti-PD-1 therapy to enhance anti-tumour immunity. However, the functional mechanisms and therapeutic implications of this axis in hepatocellular carcinoma (HCC) remain insufficiently characterised. Our study employed a multi-omics approach integrating multiple layers-transcriptomic, mutational, immune and regulatory-to understand the functional roles of the CD47-SIRPα axis. Pan-cancer analyses of expression patterns and prognostic significance identified the CD47-SIRPα axis as a negative prognostic indicator in HCC, where the cellular heterogeneity of CD47 expression was mapped by its subcellular localisation patterns and somatic mutation profiles. Functional analyses revealed that high CD47 expression modulated cancer stemness and lipid metabolism in HCC. Furthermore, it remodeled the tumour immune micro-environment, characterised by modulating M1 macrophage polarization and elevated expression of immune checkpoints. The protein-protein interaction (PPI) network combined with structural bioinformatics analyses identified SIRPG and SIRPB1 as additional high-probability direct interaction partners of CD47. Biomarker relevance analysis showed that CD47 demonstrated predictive capacity in 15 cohorts, and drug sensitivity profiling identified epigenetic modulators and metabolic regulators as potential candidates for CD47-targeted combination therapy. Through expression profiling, correlation assessment and survival evaluation, we identified that the FGD5-AS1/miR-22-3p axis was the most potent upstream non-coding RNA regulatory pathway for CD47 in HCC. Our findings systematically characterise the CD47-SIRPα axis as a negative prognostic indicator and an immunotherapeutic target in HCC.