Mechanistic Basis and Therapeutic Potential of a Novel TXNIP Inhibitor in Diabetes Treatment.

Recently, inhibiting thioredoxin-interacting protein (TXNIP), a protein that plays critical roles in glucose metabolism, has emerged as a promising therapeutic strategy for diabetes. Through screening a compound library using a TXNIP reporter system, we identified an orally bioavailable small molecule (SKL-1223) that exhibits an excellent safety profile and potent glucose-lowering effects in streptozotocin-induced and db/db murine models. Notably, SKL-1223 promotes beta-cell formation and loss of alpha-cells in these disease models. Mechanistic studies indicate that SKL-1223 ameliorates hyperglycemia by directly modulating TXNIP transcription through attenuation of transcription factor binding. Compared with current therapies, SKL-1223 demonstrates improved efficacy in suppressing glucagon-mediated hepatic gluconeogenesis in diabetes treatment. Together, our findings not only identify a novel TXNIP inhibitor for controlling glucose production but also position SKL-1223 as a first-in-class therapeutic candidate addressing an unmet need in diabetes management.