Introduction <p>Biologic drug survival in psoriasis is variable. While clinical factors such as obesity and comorbidities contribute to early discontinuation, genetic predictors are less defined. The ZMIZ1/TGF-β/STAT axis regulates immune–metabolic responses and represents a promising pharmacogenetic target.</p> Methods <p>We retrospectively analyzed 875 biologic treatment courses from 312 patients with moderate-to-severe psoriasis (NCT07041112). A pathway-based genetic score was derived from seven single nucleotide polymorphisms (SNPs) in the ZMIZ1/TGF-β/STAT axis and dichotomized at the median. The primary outcome was time to biologic discontinuation, assessed with Kaplan–Meier curves and Cox proportional hazards models adjusted for demographic, clinical, and inflammatory covariates.</p> Results <p>Patients with a high genetic score had significantly longer drug survival (hazard ratio [HR] = 0.74; 95% confidence interval [CI]: 0.62–0.89; <i>p</i> = 0.0015), despite elevated baseline tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-15, and leptin. This indicates that genetic background simultaneously conditioned immune–metabolic activation and treatment persistence. Predictive value was strongest for anti-IL12/23 agents (HR = 0.44; 95% CI: 0.26–0.75; <i>p</i> = 0.002) and anti-TNF therapies (HR = 0.79; 95% CI: 0.62–0.99; <i>p</i> = 0.045), but absent for anti-IL17/IL-23 agents after adjustment. None of the circulating biomarkers independently predicted survival.</p> Conclusion <p>A functional genetic score in the ZMIZ1/TGF-β/STAT pathway independently predicted long-term biologic persistence in psoriasis, particularly with anti-TNF and anti-IL12/23 therapies. Its association with immune–metabolic activation suggests that genetic background shapes both inflammatory status and treatment durability. Incorporating such profiling into predictive algorithms may improve treatment personalization and biologic retention.</p> Trial Registration <p>Trial Registration NCT07041112.</p>