Aflatoxin B1 accelerates diabetic nephropathy progression via ITGA11/LTBP1-dependent oxidative and fibrotic pathways:...

Environmental toxicants are increasingly recognized as potential modifiers of diabetic nephropathy (DN) progression. Aflatoxin B1 (AFB1), a ubiquitous foodborne contaminant, can induce oxidative and fibrotic injury, yet its DN-relevant molecular circuitry has not been systematically mapped.

To define DN-associated, AFB1-responsive pathways and prioritize mechanistically plausible molecular mediators and intercellular communication axes linked to profibrotic remodeling.

We integrated bulk transcriptomics with single-cell and spatial transcriptomics, immune deconvolution, cell-cell communication inference, pseudotime trajectory analysis, and structure-informed modeling (molecular docking and molecular dynamics simulations).

AFB1-associated signatures were enriched for oxidative stress, xenobiotic metabolism, and extracellular matrix (ECM) remodeling programs. Cross-cohort analyses prioritized ITGA11 and LTBP1 as consistently AFB1-responsive candidates with diagnostic performance (AUC >0.7), and spatial/single-cell mapping localized their expression predominantly to mesangial and fibroblast-like compartments. Pseudotime trajectories suggested distinct dynamics, with transient ITGA11 activation and sustained LTBP1 upregulation, consistent with complementary roles during ECM remodeling. Cell-cell communication analysis highlighted a glomerular PTHLH-PTH1R signaling axis between podocyte- and mesangial-associated states, and immune profiling linked ITGA11/LTBP1-associated programs to innate/adaptive immune reprogramming. In silico modeling supported direct AFB1-protein interactions, with stable binding observed over 100-ns simulations and higher predicted affinity toward ITGA11 (≈-8.4 kcal/mol).

Collectively, our results suggest that AFB1 may aggravate DN by coupling oxidative/immune stress to mesangial- and fibroblast-centered ECM remodeling. ITGA11/LTBP1 and the glomerular PTHLH-PTH1R signaling axis therefore merit focused investigation as priority nodes to delineate the mechanistic basis of AFB1-driven nephrotoxicity in DN, including intercellular injury amplification within the glomerular unit.