Multi-omics integration identifies cell-type-specific CISD1 and QDPR as druggable regulators linking hepatocellular
Longyang Sun1, Junjie Bi1, Jianguang Sun1
1Shandong University of Traditional Chinese Medicine,Jinan, 250011 China.
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.
Insights
Hepatocellular carcinoma (HCC) and major depressive disorder (MDD) share genetic links through CISD1 and QDPR genes. Dihydroergotamine shows potential for treating both conditions simultaneously.
Area of Science:
- Genetics and Genomics
- Pharmacology
- Oncology
- Psychiatry
Background:
- Hepatocellular carcinoma (HCC) and major depressive disorder (MDD) frequently co-occur.
- The underlying shared biological mechanisms and potential for common therapeutic targets remain largely unexplored.
Purpose of the Study:
- To identify druggable genes with shared causal effects in both HCC and MDD.
- To elucidate the mediating pathways and validate potential therapeutic compounds for this comorbidity.
Main Methods:
- A three-step Mendelian randomization strategy was employed, including eQTL screening and refinement.
- 2,534 druggable genes were systematically screened for shared causal effects.
- Mediating pathways were analyzed using inflammatory proteins and cerebrospinal fluid metabolites, with molecular docking for compound validation.
Main Results:
- Two genes, CISD1 and QDPR, met stringent criteria for shared genetic influence.
- Specific immune cell expression patterns of CISD1 and QDPR were associated with altered risk for HCC and MDD.
- Metabolites alpha-hydroxyisovalerate and N-acetyl-β-alanine mediated the effects of CISD1 and QDPR, respectively.
- Dihydroergotamine demonstrated high binding affinity for both CISD1 and QDPR proteins.
Conclusions:
- CISD1 and QDPR are genetically supported, druggable regulators linking metabolic and inflammatory pathways in HCC-MDD comorbidity.
- Repurposing the FDA-approved drug dihydroergotamine presents a promising avenue for simultaneous treatment of HCC and MDD, warranting preclinical investigation.
