Orchestrating cell death and microenvironment: Natural products as multi-target modulators of pyroptosis in myocardial ischemia-reperfusion injury
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Published on: November 28, 2025
Rong Liu1, Xiaobo Feng1, Hongyun Ji1
1Department of Cardiology, Zhangjiagang Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, Jiangsu 215600, China.
Abstract:
Myocardial ischemia-reperfusion injury (MIRI) is a serious clinical problem. Pyroptosis is a metabolic inflammation linking mechanism to MIRI as of now. The clinical translation of single-target synthetic inhibitors has been limited by off-target toxicity and their inability to halt the complex compensatory signaling of cell death despite mechanistic advances. The current review aims to tackle the translational bottlenecks through an integration of the evolving landscape of pyroptosis and PANoptosis network and multicellular microenvironmental crosstalk beyond isolated pathways. We consider natural bioactive products as superior therapeutic candidates, as they are not just inhibitors but pleiotropic system regulators. Unlike synthetic agents, these do exhibit synergy across processes such as metabolism, epigenetics, and immunity. Additionally, we propose integration with organelle-targeted nanomedicine to overcome the natural compounds' inherent pharmacokinetic limitations. Through a paradigm shift from single-target blockade to multi-dimensional network regulation through precision delivery, using this review offers a roadmap for developing next-generation cardioprotective strategies.
Insights
Myocardial ischemia-reperfusion injury (MIRI) involves pyroptosis. Natural compounds and nanomedicine offer a multi-dimensional network regulation strategy for novel cardioprotective therapies, overcoming limitations of single-target inhibitors.
Area of Science:
- Biomedical Science
- Cardiovascular Research
- Molecular Medicine
Background:
- Myocardial ischemia-reperfusion injury (MIRI) presents significant clinical challenges.
- Pyroptosis, a form of programmed cell death, is increasingly recognized as a key inflammatory mediator in MIRI.
- Current single-target synthetic inhibitors face limitations due to off-target toxicity and inability to address complex cell death signaling.
Purpose of the Study:
- To review and integrate the roles of pyroptosis and PANoptosis networks in MIRI.
- To explore the potential of natural bioactive products as pleiotropic regulators for MIRI.
- To propose a novel therapeutic strategy combining natural products with organelle-targeted nanomedicine for enhanced cardioprotection.
Main Methods:
- Comprehensive literature review integrating pyroptosis, PANoptosis, and microenvironmental crosstalk in MIRI.
- Analysis of natural bioactive products as system regulators beyond simple inhibition.
- Conceptual integration of nanomedicine for improved pharmacokinetics of natural compounds.
Main Results:
- Natural bioactive products demonstrate pleiotropic effects, regulating metabolism, epigenetics, and immunity synergistically.
- Integration with organelle-targeted nanomedicine can overcome pharmacokinetic limitations of natural compounds.
- A shift from single-target blockade to multi-dimensional network regulation is proposed.
Conclusions:
- Natural products and nanomedicine offer a promising, multi-dimensional approach to MIRI treatment.
- This integrated strategy provides a roadmap for developing next-generation cardioprotective agents.
- Addressing the complex interplay of cell death pathways and microenvironment is crucial for effective MIRI therapy.
