ROS-NLRP3 Inflammasome Axis in Obesity: A Critical Review of Oxidative Stress-Driven Inflammation and Emerging Therapeutic Strategies.
- 1Department of Biopharmaceuticals, Catholic Sangji University, Andong 36686, Republic of Korea.
- 2College of Pharmacy, Gachon University, Incheon 21936, Republic of Korea.
- 3Department of Oriental Medicinal Biotechnology, College of Life Sciences, Kyung Hee University, Yongin 17104, Republic of Korea.
Abstract
Background and Objectives: Obesity is a chronic, low-grade inflammatory state. Oxidative stress and reactive oxygen species (ROS) are increasingly recognized as not just passive byproducts but also signaling contributors to metabolic dysfunction in obesity. Among the inflammatory effectors that interact with ROS, the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome has emerged as an important node linking metabolic stress to interleukin (IL)-1β/IL-18-mediated inflammation and insulin resistance. This review critically examines the ROS-NLRP3 axis as a mechanistic framework for obesity progression, weighing supporting against contradictory evidence and defining translational opportunities. Materials and Methods: A narrative concept-driven review was conducted by searching PubMed, Scopus, and Web of Science throughout August 2026, prioritizing mechanistic, human, and interventional studies of ROS, mitochondrial ROS (mtROS), NLRP3 activation, and obesity, with deliberate inclusion of discordant findings. Results: ROS-dependent NF-κB signaling contributes to NLRP3 priming, whereas mtROS, oxidized mitochondrial DNA, and thioredoxin-interacting protein (TXNIP) are consistently implicated in NLRP3 activation and caspase-1-dependent maturation of IL-1β and IL-18, which are associated with adipose tissue inflammation and impaired insulin signaling. However, loss-of-function studies have yielded inconsistent metabolic protection; human evidence is largely observational, and NLRP3 inhibitors, such as MCC950, carry organ-specific toxicities, indicating context dependence rather than a simple linear pathway. Upstream (mitochondria-targeted antioxidants, TXNIP blockade), core (selective NLRP3 inhibitors), and downstream (IL-1β/IL-18 blockade) strategies are supported mainly by preclinical or early clinical data; for metformin, SGLT2 inhibitors, and GLP-1 receptor agonists, ROS/NLRP3 modulation is a potentially relevant contributory mechanism. Conclusions: The ROS-NLRP3 axis provides a useful mechanistic framework for obesity-associated inflammation, but human causal evidence is limited, and its contribution is tissue-, stage-, and context-dependent; therefore, human-validated, mechanism-based studies are needed.
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BibTeX
@article{ahn2026rosnlrp3,
title = {{ROS-NLRP3 Inflammasome Axis in Obesity: A Critical Review of Oxidative Stress-Driven Inflammation and Emerging Therapeutic Strategies.}},
author = {Sungeun Ahn and SangMin Park and Shakina Yesmin Simu},
journal = {Medicina (Kaunas, Lithuania)},
year = {2026},
month = oct,
doi = {10.3390/medicina62101969},
url = {https://europepmc.org/article/MED/42942500},
note = {CC BY},
}
RIS
TY - JOUR
TI - ROS-NLRP3 Inflammasome Axis in Obesity: A Critical Review of Oxidative Stress-Driven Inflammation and Emerging Therapeutic Strategies.
AU - Sungeun Ahn
AU - SangMin Park
AU - Shakina Yesmin Simu
PY - 2026
DA - 2026/10/12
JO - Medicina (Kaunas, Lithuania)
DO - 10.3390/medicina62101969
UR - https://europepmc.org/article/MED/42942500
AB - Background and Objectives: Obesity is a chronic, low-grade inflammatory state. Oxidative stress and reactive oxygen species (ROS) are increasingly recognized as not just passive byproducts but also signaling contributors to metabolic dysfunction in obesity. Among the inflammatory effectors that interact with ROS, the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome has emerged as an important node linking metabolic stress to interleukin (IL)-1β/IL-18-mediated inflammation and insulin resistance. This review critically examines the ROS-NLRP3 axis as a mechanistic framework for obesity progression, weighing supporting against contradictory evidence and defining translational opportunities. Materials and Methods: A narrative concept-driven review was conducted by searching PubMed, Scopus, and Web of Science throughout August 2026, prioritizing mechanistic, human, and interventional studies of ROS, mitochondrial ROS (mtROS), NLRP3 activation, and obesity, with deliberate inclusion of discordant findings. Results: ROS-dependent NF-κB signaling contributes to NLRP3 priming, whereas mtROS, oxidized mitochondrial DNA, and thioredoxin-interacting protein (TXNIP) are consistently implicated in NLRP3 activation and caspase-1-dependent maturation of IL-1β and IL-18, which are associated with adipose tissue inflammation and impaired insulin signaling. However, loss-of-function studies have yielded inconsistent metabolic protection; human evidence is largely observational, and NLRP3 inhibitors, such as MCC950, carry organ-specific toxicities, indicating context dependence rather than a simple linear pathway. Upstream (mitochondria-targeted antioxidants, TXNIP blockade), core (selective NLRP3 inhibitors), and downstream (IL-1β/IL-18 blockade) strategies are supported mainly by preclinical or early clinical data; for metformin, SGLT2 inhibitors, and GLP-1 receptor agonists, ROS/NLRP3 modulation is a potentially relevant contributory mechanism. Conclusions: The ROS-NLRP3 axis provides a useful mechanistic framework for obesity-associated inflammation, but human causal evidence is limited, and its contribution is tissue-, stage-, and context-dependent; therefore, human-validated, mechanism-based studies are needed.
SN - 1010-660X
SN - 1648-9144
ER -