Frontiers in pharmacology · 2026
Scutellarein promotes diabetic wound repair and preserves fibroblast calcium-mitochondrial homeostasis.
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Huang Yizhuo, Shan Shengzhou, Chang Mengling, Liu Yi, Yao Yucheng, Yang Jun, Liu Fei
Аннотация
BACKGROUND: Diabetic wounds are characterized by delayed repair associated with persistent inflammation, oxidative stress, fibroblast dysfunction, mitochondrial injury, and impaired angiogenesis. Scutellarein (SCU), a structurally defined plant-derived flavonoid metabolite, has documented antioxidant and anti-inflammatory activities; however, its role and the mechanistically relevant pathways engaged in diabetic wound repair, particularly those involving calcium-mitochondrial homeostasis and purinergic signaling, remain incompletely defined.
METHODS: We administered local SCU in a streptozotocin-induced diabetic mouse cutaneous wound model and, in H 2 O 2 -injured L929 fibroblasts, assessed scratch closure, survival, redox balance, mitochondrial morphology and function, and calcium overload. We then used RNA sequencing (RNA-seq) and adenosine triphosphate (ATP) challenge/reversal experiments to examine purinergic calcium signaling. These analyses identified P2rx1-the gene encoding P2RX1 (P2X purinoceptor 1), an ATP-gated cation channel that mediates rapid calcium entry-as a candidate purinergic signal rather than a validated target.
RESULTS: SCU accelerated wound closure and increased re-epithelialization, Masson-positive collagen deposition, proliferative α -SMA-positive wound cells, and angiogenic indices in diabetic wounds. In injured fibroblasts, SCU increased scratch closure, reduced cell death and reactive oxygen species (ROS) accumulation, restored the superoxide dismutase (SOD)/malondialdehyde (MDA) balance, preserved mitochondrial morphology and membrane potential, and increased cellular ATP content. RNA-seq showed P2rx1 downregulation after SCU treatment and enrichment of calcium transport, mitochondrial, inflammatory, and wound-healing pathways. ATP addition attenuated the SCU-associated reductions in calcium overload, mitochondrial depolarization, and inflammatory gene expression, consistent with a contribution from broad purinergic calcium signaling.
CONCLUSION: In experimental models, SCU promoted diabetic wound repair and protected fibroblasts from oxidative injury. The data support preservation of calcium-mitochondrial homeostasis as a mechanistically relevant axis, and broad purinergic signaling, possibly involving P2RX1, may contribute to these effects; direct receptor-perturbation studies are warranted.
METHODS: We administered local SCU in a streptozotocin-induced diabetic mouse cutaneous wound model and, in H 2 O 2 -injured L929 fibroblasts, assessed scratch closure, survival, redox balance, mitochondrial morphology and function, and calcium overload. We then used RNA sequencing (RNA-seq) and adenosine triphosphate (ATP) challenge/reversal experiments to examine purinergic calcium signaling. These analyses identified P2rx1-the gene encoding P2RX1 (P2X purinoceptor 1), an ATP-gated cation channel that mediates rapid calcium entry-as a candidate purinergic signal rather than a validated target.
RESULTS: SCU accelerated wound closure and increased re-epithelialization, Masson-positive collagen deposition, proliferative α -SMA-positive wound cells, and angiogenic indices in diabetic wounds. In injured fibroblasts, SCU increased scratch closure, reduced cell death and reactive oxygen species (ROS) accumulation, restored the superoxide dismutase (SOD)/malondialdehyde (MDA) balance, preserved mitochondrial morphology and membrane potential, and increased cellular ATP content. RNA-seq showed P2rx1 downregulation after SCU treatment and enrichment of calcium transport, mitochondrial, inflammatory, and wound-healing pathways. ATP addition attenuated the SCU-associated reductions in calcium overload, mitochondrial depolarization, and inflammatory gene expression, consistent with a contribution from broad purinergic calcium signaling.
CONCLUSION: In experimental models, SCU promoted diabetic wound repair and protected fibroblasts from oxidative injury. The data support preservation of calcium-mitochondrial homeostasis as a mechanistically relevant axis, and broad purinergic signaling, possibly involving P2RX1, may contribute to these effects; direct receptor-perturbation studies are warranted.