Crosstalk Between Ferroptosis, Pyroptosis, and PANoptosis in Neurological Disorders: Molecular Mechanisms and Pharmacological Modulation by Natural Products

Abstract

AbstractNeurological disorders—including cerebral ischemia, Alzheimer’s disease, traumatic brain injury, epilepsy, and glioblastoma—share oxidative stress, neuroinflammation, and programmed cell death as common pathogenic drivers. Emerging evidence shifts focus from classical apoptosis to three alternative regulated cell death pathways: ferroptosis (iron‑dependent lipid peroxidation), pyroptosis (inflammasome‑mediated lysis), and PANoptosis (concurrent interaction of multiple pathways on a shared platform). These pathways are not mutually exclusive; they crosstalk via reactive oxygen species, mitochondrial dysfunction, iron dyshomeostasis, and NF‑κB signaling. This review synthesizes current knowledge on their molecular interconnections in neurological diseases. We further explore how natural products and herbal formulas—curcumin, mangiferin, rhynchophylline, quercetin, paeonol, and traditional Chinese medicine decoctions—modulate these pathways to confer neuroprotection. Network pharmacology and multi‑omics strategies that decipher the multi‑target mechanisms of these agents are also discussed. By integrating cellular, animal, and in silico evidence, we propose that simultaneous inhibition of ferroptosis, pyroptosis, and PANoptosis by natural products represents a promising therapeutic strategy. Future directions include dual‑target compounds, stem cell combinations, and biomarker‑guided clinical trials. Keywords: Ferroptosis; Pyroptosis; PANoptosis; Natural products; Neurological disorders; Crosstalk; Neuroinflammation; Oxidative stress