COL6A3 and obesity due to melanocortin 4 receptor deficiency: In conclusion, by integrating two-step proteome-wide MR, colocalization, observational assessments, epigenomics, and single-cell RNA sequencing, we identified five actionable mediators of obesity’s effect on cardiometabolic diseases and prioritized COL6A3-derived endotrophin as a therapeutic target to reduce CAD risk.