Multi-omics integration identifies cell-type-specific CISD1 and QDPR as druggable regulators linking hepatocellular carcinoma and major depressive disorder

Background
Hepatocellular carcinoma (HCC) and major depressive disorder (MDD) often co-occur, but whether this comorbidity reflects shared pharmacologically tractable biology remains unclear.
Methods
We integrated a three-step mendelian randomization strategy—comprising whole-blood eQTL screening, GTEx eQTL validation, and single-cell immune eQTL refinement—to systematically screen 2,534 druggable genes, to identify targets with consistent causal effects across two diseases. Subsequently, we dissected their potential mediating pathways using 91 circulating inflammatory proteins and 338 cerebrospinal fluid metabolites as mediators, and subsequently validated repurposable compounds via molecular docking.
Results
Two genes satisfied all stringent criteria: CISD1and QDPR. Immune-cell-specific expression patterns of CISD1 in CD4 NC, CD8 ET, and NK cells increased shared risk, whereas QDPR transcription in CD4 ET, CD4 NC, CD8 ET, Mono C, and NK R cells reduced risk. Alpha-hydroxyisovalerate mediated 6.98% (HCC) and 8.75% (MDD) of CISD1’s causal effect; N-acetyl-β-alanine accounted for 16.15% (HCC) and 8.13% (MDD) of QDPR’s protective effect. Dihydroergotamine, an FDA-approved antimigraine agent, exhibited high binding affinity for both proteins (−9.3 and −10.2 kcal mol⁻¹), nominating it as a dual-indication candidate.
Conclusions
CISD1and QDPRconstitute genetically supported, druggable regulators that converge mechanistically on metabolic–inflammatory axes associated with HCC–MDD comorbidity. Repurposing dihydroergotamine warrants immediate preclinical evaluation for simultaneous oncologic and psychiatric benefits.