Therapeutic Target Discovery for Multiple Myeloma: Identifying Druggable Genes via Mendelian Randomization DOI Creative Commons
Shijun Jiang, Fengjuan Fan, Qun Li

et al.

Biomedicines, Journal Year: 2025, Volume and Issue: 13(4), P. 885 - 885

Published: April 5, 2025

Background: Multiple myeloma (MM) is a hematological malignancy originating from the plasma cells present in bone marrow. Despite significant therapeutic advancements, relapse and drug resistance remain major clinical challenges, highlighting urgent need for novel targets. Methods: To identify potential druggable genes associated with MM, we performed Mendelian randomization (MR) analysis. Causal candidates were further validated using single-tissue transcriptome-wide association study (TWAS), colocalization analysis was conducted to assess shared genetic signals between gene expression disease risk. Potential off-target effects assessed through an MR phenome-wide (MR-PheWAS). Additionally, molecular docking functional assays used evaluate candidate efficacy. Results: The identified nine (FDR < 0.05), among which Orosomucoid 1 (ORM1) Oviductal Glycoprotein (OVGP1) supported by both TWAS evidence (PPH4 > 0.75). Experimental validation demonstrated downregulation of ORM1 OVGP1 MM (p 0.05). Pregnenolone irinotecan, as agonists OVGP1, respectively, significantly inhibited cell viability, while upregulating their Conclusions: Our highlights targets MM. efficacy pregnenolone irinotecan suppressing growth suggests application. These findings provide insights into pathogenesis offer promising strategy overcoming resistance.

Language: Английский

Therapeutic Target Discovery for Multiple Myeloma: Identifying Druggable Genes via Mendelian Randomization DOI Creative Commons
Shijun Jiang, Fengjuan Fan, Qun Li

et al.

Biomedicines, Journal Year: 2025, Volume and Issue: 13(4), P. 885 - 885

Published: April 5, 2025

Background: Multiple myeloma (MM) is a hematological malignancy originating from the plasma cells present in bone marrow. Despite significant therapeutic advancements, relapse and drug resistance remain major clinical challenges, highlighting urgent need for novel targets. Methods: To identify potential druggable genes associated with MM, we performed Mendelian randomization (MR) analysis. Causal candidates were further validated using single-tissue transcriptome-wide association study (TWAS), colocalization analysis was conducted to assess shared genetic signals between gene expression disease risk. Potential off-target effects assessed through an MR phenome-wide (MR-PheWAS). Additionally, molecular docking functional assays used evaluate candidate efficacy. Results: The identified nine (FDR < 0.05), among which Orosomucoid 1 (ORM1) Oviductal Glycoprotein (OVGP1) supported by both TWAS evidence (PPH4 > 0.75). Experimental validation demonstrated downregulation of ORM1 OVGP1 MM (p 0.05). Pregnenolone irinotecan, as agonists OVGP1, respectively, significantly inhibited cell viability, while upregulating their Conclusions: Our highlights targets MM. efficacy pregnenolone irinotecan suppressing growth suggests application. These findings provide insights into pathogenesis offer promising strategy overcoming resistance.

Language: Английский

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