Regulated cell death in cerebral infarction: a switch-aware framework from molecular mechanisms to targeted therapy

Background Cerebral infarction remains a leading cause of death and long-term disability. Although reperfusion therapy has transformed early management, its benefit is limited by narrow time windows, and most neuroprotective monotherapies have failed in translation. Rather than isolated endpoints, apoptosis, necroptosis, pyroptosis, ferroptosis and autophagy-related processes form a dynamically interconnected network; cuproptosis remains an exploratory candidate. Methods This narrative synthesis (not a systematic/meta-analysis) drew on primary research and authoritative nomenclature sources on the major regulated cell death modalities in cerebral ischemia/reperfusion, retrieved from PubMed, Embase, and Web of Science through August 2026. The search was not pre-registered, and no formal risk-of-bias assessment was performed. Results Post-ischemic cell death is organized around three convertible molecular switch hubs—caspase-8/RIPK, NCOA4ferritinophagy, and Nrf2 — with gasdermin-D (GSDMD)-mediated pyroptosis as a downstream effector. These hubs map onto the ischemic core, penumbra, and reperfused territory over 0–72 h, and their interconversion helps explain the limited efficacy of single-executor monotherapies. We further assess biomarkers and pharmacological interventions, and extend the framework through the gut-brain axis, where intestinal barrier dysfunction and dysbiosis prime the same central NLRP3, RIPK, and Nrf2 switches. Cuproptosis is retained only as a hypothesis-generating candidate. Clinically meaningful neuroprotection will require mechanism-based, time-and compartment-specific combination strategies. Modality-specific composite biomarker panels paired with time-sensitive therapies offer the most tractable route to patient stratification; the gut-derived input requires prospective validation. Conclusion Framing post-ischemic cell death through convertible switches reframes neuroprotection as a problem of network timing and patient stratification. This switch-aware framework is prospective and falsifiable, generating testable hypotheses for future preclinical and clinical studies.