Soluble tumor necrosis factor receptors in diabetes: risk sensing and receptor-resolved targeting.

Diabetes drives a major burden of kidney failure, cardiovascular disease, and premature mortality, yet current clinical markers incompletely capture individual trajectories of organ decline. Soluble tumor necrosis factor receptors 1 and 2 (sTNFR1/2) have emerged as among the most reproducible circulating predictors of diabetic kidney disease progression, retaining prognostic value after adjustment for estimated glomerular filtration rate (eGFR) and albuminuria across multiple cohorts. Prospective studies in type 2 diabetes also associate higher sTNFR1/2 with incident cardiovascular events and all-cause mortality, supporting a systemic risk phenotype that is not fully explained by baseline kidney measures. Mechanistically, recent work has refined the classical view of tumor necrosis factor (TNF) as a generic inflammatory mediator by identifying proximal checkpoints that govern TNFR1 "injury-biased" outputs, including ubiquitination- and lipidation-dependent control of RIPK1, trafficking-dependent restraint of death-receptor signaling, and cross-pathway phosphorylation that retunes downstream complex assembly. In parallel, advances in therapeutic engineering are shifting the field from non-selective TNF neutralization toward receptor-selective modulation, including TNFR1-selective antagonists, allosteric inhibitors, and shedding strategies designed to reduce injury signaling while preserving TNFR2-linked immunoregulatory and reparative programs. This receptor-resolved framework provides a coherent basis for interpreting why soluble receptors outperform circulating TNF as prognostic biomarkers and for developing mechanism-informed interventions in diabetes.