The Inhibition of Oxidative Stress-Mediated Cell Apoptosis by the Caspase Inhibitor (S)-3-((S)-2-(6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxoisoindolin-2-yl)butanamido)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic Acid in Human Dermal Papilla Cells

Abstract

Alopecia is traditionally viewed as androgen-dependent, but emerging evidence has implicated oxidative stress in the pathogenesis of hair loss. Current treatments for alopecia have limited efficacy, leading to the need for new therapies. Human dermal papilla cells (hDPCs) play a pivotal role in hair follicle (HF) development and hair growth regulation. In this study, we investigated the potential of (S)-3-((S)-2-(6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxoisoindolin-2-yl)butanamido)-4-oxo-5-(2,3,5,6 tetrafluorophenoxy) pentanoic acid (THPA), a pan-caspase inhibitor, to reduce ROS-induced cellular damage and apoptosis in hDPCs. Our study revealed that THPA effectively suppressed hydrogen peroxide-induced apoptosis while also attenuating activated caspase signaling. Additionally, THPA restored the down-regulated expression of β-catenin, a key mediator of the Wnt/β-catenin pathway, in hDPCs exposed to hydrogen peroxide. Furthermore, significant alterations in Akt/mTOR/p70S6K signaling were observed following THPA treatment. Notably, THPA treatment led to a reduction in the expression of Dickkopf-1 (DKK-1), an inhibitor of the Wnt/β-catenin pathway implicated in hair follicle regression. Moreover, THPA treatment decreased the expression of the cell senescence markers p21 and p16, suggesting a potential role in preserving hDPC function and delaying hair follicle regression. Collectively, our findings highlight the therapeutic potential of THPA in preventing hair loss by protecting hDPCs against oxidative stress damage.