Prostaglandin E₂ (PGE₂) is known to be effective in regenerating tissues, and bimatoprost, an analog of PGF_2α, has been approved by the FDA as an eyelash growth promoter and has been proven effective in human hair follicles. Thus, to enhance PGE₂ levels while improving hair loss, we found dihydroisoquinolinone piperidinylcarboxy pyrazolopyridine (DPP), an inhibitor of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), using DeepZema^®, an AI-based drug development program. Here, we investigated whether DPP improved hair loss in human follicle dermal papilla cells (HFDPCs) damaged by dihydrotestosterone (DHT), which causes hair loss. We found that DPP enhanced wound healing and the expression level of alkaline phosphatase in DHT-damaged HFDPCs. We observed that DPP significantly down-regulated the generation of reactive oxygen species caused by DHT. DPP recovered the mitochondrial membrane potential in DHT-damaged HFDPCs. We demonstrated that DPP significantly increased the phosphorylation levels of the AKT/ERK and activated Wnt signaling pathways in DHT-damaged HFDPCs. We also revealed that DPP significantly enhanced the size of the three-dimensional spheroid in DHT-damaged HFDPCs and increased hair growth in ex vivo human hair follicle organ culture. These data suggest that DPP exhibits beneficial effects on DHT-damaged HFDPCs and can be utilized as a promising agent for improving hair loss.

Prostaglandin D₂ (PGD₂) levels are high in the balding areas of human scalps, and PGD₂ has been found to inhibit hair growth. It is known that the inhibition of the PGD₂ receptor can promote hair growth by preventing hair follicles from entering the catagen phase. Thus, we identified an antagonist of DP2, the receptor for PGD2, as a potential treatment for hair loss using an AI-based DeepZema^® drug development program. In this study, we identified that the DP₂ antagonist (DP2A) could ameliorate alopecia in human follicle dermal papilla cells (HFDPCs) that were stimulated by dihydrotestosterone (DHT), a known molecule related to hair loss. We observed that the DP2A promoted wound healing efficiency and increased alkaline phosphatase levels in the HFDPCs that were damaged with DHT. In addition, we found that the DP2A diminished the reactive oxygen species (ROS) levels generated in the DHT-damaged HFDPCs. We confirmed that the DP2A effectively recovered the membrane potential of mitochondria in these cells. We also demonstrated that the DP2A enhanced the phosphorylation levels of both Akt and ERK in the HFDPCs that were damaged with DHT. Notably, we revealed that the DP2A slightly enlarged the three-dimensional spheroid size in these cells and confirmed that the DP2A improved hair growth in the organ culture of human hair follicles. Taken together, we suggest that DP2A has therapeutic effects on HFDPCs that are damaged by DHT and holds promise as a potential treatment for treating hair loss.

Androgenetic alopecia (AGA) is closely associated with oxidative stress and vascular dysfunction, which disrupt nutrient delivery to hair follicles and promote follicle miniaturization. Dihydrotestosterone (DHT) exposure impairs human dermal microvascular endothelial cell (HDMEC) function by inducing mitochondrial disruption, excessive reactive oxygen species (ROS) accumulation, and reduced angiogenic capacity. This study evaluated the protective effects of dihydroisoquinolinone piperidinylcarboxy pyrazolopyridine (DPP), a novel 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitor identified through the AI-based discovery platform DeepZema^®, in DHT-exposed HDMECs. DPP markedly reduced intracellular and mitochondrial ROS levels, restored mitochondrial membrane potential, and increased ATP production, thereby alleviating oxidative stress and supporting mitochondrial function. DPP also enhanced endothelial cell migration and capillary-like tube formation, demonstrating the restoration of angiogenic capacity that is essential for sustaining perifollicular vascularization. Moreover, DPP mitigated stress-associated signaling by reducing the phosphorylation of ERK, JNK, and p38 within the MAPK pathway, thereby suggesting the reestablishment of endothelial homeostasis under DHT-induced stress. Collectively, these findings indicate that DPP preserves endothelial function under DHT-driven oxidative conditions. We suggest that DPP may exert complementary protective effects on both vascular and follicular compartments, supporting its potential relevance in hair follicle regeneration.

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.

Conventional treatments for androgenetic alopecia (AGA) are often limited by suboptimal efficacy and potential adverse effects, highlighting the need for alternative approaches. We aimed to evaluate the efficacy and safety of a multi-targeted cosmetic formulation containing TrinogeniX™, composed of synthetic small-molecule inhibitors of glycogen phosphorylase, the prostaglandin D₂ receptor, and 15-hydroxyprostaglandin dehydrogenase, developed using the artificial intelligence-driven platform DeepZema^®, in individuals with AGA. This 24-week, randomized, double-blind, placebo-controlled trial involved 56 participants, of whom 49 completed the study. Efficacy was assessed using phototrichogram analysis, visual evaluation by dermatologists, and subjective questionnaires. Safety was evaluated based on adverse event reports and dermatological examinations. The test group demonstrated a significant increase in hair density and thickness over 24 weeks (p < 0.05), whereas no significant changes were observed in the placebo group. Expert visual assessments confirmed greater improvements in the test group. Subjective evaluations revealed consistently greater perceived improvements in hair loss symptoms, hair richness, and front hairline conditions in the test group. No adverse events or clinically significant abnormalities were observed. The multi-targeted cosmetic formulation (Motifull hair tonic) significantly improved hair density, thickness, and overall hair condition without adverse effects, suggesting its potential as a safe and effective option for AGA. Clinical trial registration: CRIS No. KCT0010804: A double-blind, randomized, placebo-controlled clinical trial evaluating the efficacy and safety of “Motifull Hair Tonic” (tentative name) for the alleviation of hair loss symptoms.