From NHANES to Network Pharmacology: HOMA-IR Mechanisms in Concurrent MASLD and Type 2 Diabetes

Metabolic dysfunction–associated steatotic liver disease (MASLD) and type 2 diabetes (T2D) frequently co-occur, yet the population-level role of insulin resistance remains unclear. Using NHANES 2017–2020 data (n = 1,443 U.S. adults), we examined the association between the homeostasis model assessment of insulin resistance (HOMA-IR) and concurrent MASLD–T2D, and explored putative mechanisms via network pharmacology. Each unit increase in HOMA-IR was associated with higher odds of having both MASLD and T2D versus neither condition; associations were generally stronger in females and varied by race and ethnicity. Similar patterns were observed for MASLD with prediabetes. Mediation analyses indicated that fasting plasma glucose and HbA _1c explained a substantial, but incomplete, proportion of the association, suggesting additional non-glycemic processes. Network analyses highlighted core targets (e.g., PRKACA/PRKACG, MAPK1/3, SRC, PI3K subunits) and convergent pathways including PI3K–AKT/FOXO, MAPK, AMPK and cAMP–PKA that are consistent with impaired hepatic insulin signaling and stress-responsive gluconeogenesis. Together, these findings position HOMA-IR as an integrative indicator of the MASLD–T2D comorbidity and generate mechanistic hypotheses linking epidemiologic associations to signaling networks, warranting validation in longitudinal and experimental studies.