4-Methylumbelliferone for type 1 diabetes therapy: evidence for β-cell protection via EGFR/PI3K/Akt signaling.

Authors

Shuo Yang, Shanshan Zhu, Xinwen Yu, Wencheng Zhang, Xin Wang, Yuxin Jin, Weiting Wang, Guohong Zhao, Bin Gao

Published in

Journal of endocrinological investigation. Jun 29, 2026. Epub Jun 29, 2026.

Abstract

Type 1 diabetes mellitus (T1DM) results from autoimmune-mediated destruction of pancreatic β-cells, leading to absolute insulin deficiency. Current treatments rely on insulin replacement and do not prevent β-cell loss. 4-Methylumbelliferone (4-MU), an inhibitor of hyaluronan synthesis, has shown anti-inflammatory and cytoprotective effects, but its therapeutic potential and mechanisms in T1DM remain unclear.
A streptozotocin (STZ)-induced mouse model of T1DM was treated with 4-MU for three weeks. Blood glucose levels and glucose tolerance were evaluated. Pancreatic islet morphology and cell composition were assessed by immunofluorescence. In parallel, STZ -injured MIN6 and βTC6 β-cells were used to investigate the effects of 4-MU on cell viability, oxidative stress, intracellular Ca²⁺ homeostasis, and glucose-stimulated insulin secretion. Network pharmacology, molecular docking, qPCR, and Western blot analyses were conducted to explore the underlying mechanisms.
4-MU significantly reduced hyperglycemia and improved glucose tolerance in T1DM mice, accompanied by preservation of β-cell mass, normalization of the β/α-cell ratio, and reduced islet inflammation. In vitro, 4-MU protected β-cells from STZ-induced injury by decreasing reactive oxygen species (ROS) accumulation, restoring intracellular Ca²⁺ balance, and improving insulin secretion. Network pharmacology identified 48 shared targets between 4-MU and T1DM, with KEGG pathway enrichment highlighting the PI3K/Akt signaling pathway. Molecular docking revealed stable binding of 4-MU to key regulators, including EGFR, Akt, ESR1, INSR, and IGF1R. Consistently, 4-MU enhanced the phosphorylation of EGFR, PI3K, and Akt in injured β-cells.
4-MU exerts protective effects in T1DM by preserving pancreatic β-cells survival and function, potentially through activation of the EGFR/PI3K/Akt signaling pathway.

PMID:
42371338
Bibliographic data and abstract were imported from PubMed on 29 Jun 2026.

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