Phytomedicine : international journal of phytotherapy and phytopharmacology · 2026
Rewiring the regulated cell death network in diabetic retinopathy: natural products as system-level modulators.
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Huang Qun, Chen Tingru, Wang Fang, Wang Jieying, Fan Biying, Wu Ruolan, Wang Jinlian, Peng Shunlin, Zheng Yanlin
Аннотация
BACKGROUND: Diabetic retinopathy (DR) pathogenesis is driven by the dysregulation of an interconnected network of regulated cell death (RCD) modalities, including apoptosis, autophagy-dependent cell death, pyroptosis, and ferroptosis. Current therapies often fail to address this upstream cellular damage. Natural products (NPs), with their inherent polypharmacology, offer a promising strategy to modulate this complex network.
PURPOSE: This review advances a framework conceptualizing DR as the collapse of a dynamic RCD network and positions NPs as "RCD network modulators". We delineate how these agents can restore homeostasis and overcome the limitations of existing mono-target therapies.
METHODS: A systematic literature search was conducted using Web of Science and PubMed, integrating keywords related to "natural products", "diabetic retinopathy", and specific "regulated cell death" modalities. All animal experiments adhered to ethical guidelines and complied with both international and institutional ethical standards.
RESULTS: NPs simultaneously engage the master regulatory nodes-mitochondrial dysfunction, hyperactivation of the inflammasome, and oxidative stress. By modulating the Bcl-2 rheostat, normalizing autophagic flux, suppressing NLRP3 assembly, and activating Nrf2/SIRT1 pathways, NPs orchestrate a "network rewiring" to halt DR progression. However, clinical translation is significantly constrained by pharmacokinetic challenges, including low oral bioavailability and poor ocular penetration.
CONCLUSION: DR pathology emerges from network-level RCD dysregulation. NPs, which function as modulators of the RCD network, represent a compelling therapeutic shift toward addressing the root drivers of retinal degeneration.
PURPOSE: This review advances a framework conceptualizing DR as the collapse of a dynamic RCD network and positions NPs as "RCD network modulators". We delineate how these agents can restore homeostasis and overcome the limitations of existing mono-target therapies.
METHODS: A systematic literature search was conducted using Web of Science and PubMed, integrating keywords related to "natural products", "diabetic retinopathy", and specific "regulated cell death" modalities. All animal experiments adhered to ethical guidelines and complied with both international and institutional ethical standards.
RESULTS: NPs simultaneously engage the master regulatory nodes-mitochondrial dysfunction, hyperactivation of the inflammasome, and oxidative stress. By modulating the Bcl-2 rheostat, normalizing autophagic flux, suppressing NLRP3 assembly, and activating Nrf2/SIRT1 pathways, NPs orchestrate a "network rewiring" to halt DR progression. However, clinical translation is significantly constrained by pharmacokinetic challenges, including low oral bioavailability and poor ocular penetration.
CONCLUSION: DR pathology emerges from network-level RCD dysregulation. NPs, which function as modulators of the RCD network, represent a compelling therapeutic shift toward addressing the root drivers of retinal degeneration.