Background Scalp, nail, and palmoplantar psoriasis are termed “difficult-to-treat sites” owing to their unique anatomical features and therapeutic resistance, substantially impairing patient quality of life. Although anti-IL-17 and anti-IL-23 biologics are widely used, head-to-head comparative evidence for achieving high-level lesion clearance at these specific sites remains limited. Methods Following PRISMA-NMA guidelines, we systematically searched PubMed, Embase, and other databases from inception through November 2025 for randomized controlled trials (RCTs). Primary outcomes were defined as complete or near-complete clearance. Frequentist network meta-analysis was performed to calculate odds ratios (ORs), with treatment rankings derived from surface under the cumulative ranking curve (SUCRA) values. Results Twenty-four RCTs involving 5,946 patients and eight biologics plus placebo were included. For palmoplantar psoriasis, secukinumab ranked highest (SUCRA = 79.7%), followed by bimekizumab (72.2%) and ustekinumab (69.7%). For nail psoriasis, bimekizumab ranked first (78.9%), followed by ixekizumab (77.2%) and brodalumab (67.5%); however, local inconsistency for the ixekizumab–placebo comparison and low-certainty evidence warrant caution. For scalp psoriasis, brodalumab (87.7%) and ixekizumab (86.9%) ranked highest, followed by bimekizumab (69.0%) and guselkumab (65.1%); the brodalumab estimate relied on a single contributing study. Conclusion During induction-phase follow-up, IL-17 inhibitors tended to rank highly for complete or near-complete clearance at difficult-to-treat psoriasis sites. Bimekizumab and ixekizumab showed consistently favorable rankings across sites, but treatment selection should consider certainty of evidence, sensitivity analyses, long-term response, and patient-level factors. Systematic review registration https://www.crd.york.ac.uk/PROSPERO, identifier CRD420251271255.
Shouxu Zhang, TszLeong Lam, Yue Du et al.· Frontiers in Immunology· 0 citations
Copper is essential for mitochondrial respiration, antioxidant defense, extracellular matrix maturation, and cellular signaling, yet disturbances in its abundance or intracellular distribution can damage the kidney through mechanistically distinct pathways. Cuproptosis is a specific copper-dependent form of regulated cell death in which copper binds lipoylated mitochondrial proteins, promotes aggregation of tricarboxylic acid cycle components, destabilizes iron–sulfur cluster proteins, and elicits FDX1- and protein lipoylation-dependent proteotoxic stress. This mechanism should be distinguished from broader copper-associated injury, including redox imbalance, glutathione depletion, respiratory-chain inhibition, senescence, apoptosis, and lysyl oxidase-mediated matrix remodeling. This narrative review examines how renal copper uptake, trafficking, and compartmentalization interact with cell-specific metabolism to shape copper-related cell fates across acute kidney injury, nephrotoxicity, renal ischemia–reperfusion injury, crystal- and lipid-related tubular injury, diabetic kidney disease, podocyte injury, chronic kidney disease and renal fibrosis, end-stage renal disease, renal cell carcinoma, and hereditary copper disorders. Mechanistic evidence is strongest in selected acute tubular, crystal-injury, and renal cancer models, in which transporter manipulation, DLAT oligomerization, iron–sulfur perturbation, or functional rescue has been demonstrated. In chronic kidney disease and fibrosis, copper-DLAT interactions, complex IV inhibition, COMMD1-SOD1 dysfunction, and ATP7A-FBLN4-LOX signaling establish pathogenic copper dependence but do not yet demonstrate a complete canonical cuproptosis pathway. By integrating disease-specific evidence with the molecular determinants of copper handling and protein lipoylation, this review identifies current therapeutic opportunities, candidate biomarkers, and key research priorities while preserving the distinction between cuproptosis and other forms of copper-associated kidney injury.
Wei Shao, Qingguo Wang, Yan-Ting Liu et al.· International Journal of Mol...· 0 citations