Protective effect of pentoxifylline against high-glucose-induced ferroptosis in vascular smooth muscle cells.

Abstract: Ferroptosis has emerged as a pivotal form of regulated cell death implicated in diabetic vascular complications, yet the upstream transcriptional mechanisms governing this process remain insufficiently defined. Chronic hyperglycemia induces oxidative stress, iron overload, and vascular remodeling, but how these metabolic disturbances trigger ferroptotic signaling in vascular smooth muscle cells (VSMCs) remains unclear. In this study, we identify Krüppel-like factor 10 (KLF10) as a critical transcriptional mediator linking hyperglycemia to ferroptotic activation in VSMCs. High glucose increased KLF10 expression and enhanced its binding to the GPX4 promoter, leading to transcriptional repression of GPX4, heightened lipid peroxidation, and elevated reactive oxygen species. Pentoxifylline (PTX), a clinically used hemorheologic agent with antioxidant properties, significantly reduced ferroptosis-related lipid accumulation and partially restored GPX4 expression by suppressing KLF10 in vitro. In diabetic mice, PTX similarly attenuated dysregulation of the KLF10/GPX4 axis, lowered iron deposition, improved antioxidant enzyme activity, and mitigated vascular remodeling. Collectively, these findings establish the KLF10/GPX4 axis as a previously unrecognized regulator of diabetes-associated vascular ferroptosis and suggest that PTX may offer a promising therapeutic approach for limiting ferroptosis-driven vascular injury in diabetes.