Redefining the Evolution of Pulpal Pathology: Inflammasomes as Central Integrative Hubs and Biological Switches...

The transition from reversible to irreversible pulpitis remains inadequately defined at the molecular level. Current classifications rely largely on clinical symptoms rather than objective biological determinants, limiting diagnostic precision and therapeutic decision-making.

To integrate current experimental and translational evidence positioning inflammasomes as central molecular decision-making platforms in pulpal inflammation, and to propose a biologically grounded model in which inflammasome activation and supramolecular assembly define the threshold separating adaptive, reversible inflammation from irreversible pulpal damage, with direct clinical implications.

A structured narrative review was conducted following a comprehensive literature search of PubMed/MEDLINE, Scopus, and Web of Science from inception to December 2025. Evidence derived from in vitro systems, in vivo animal models, and analyses of human inflamed pulpal tissues was synthesised to characterise inflammasome sensors, adaptor and effector components, regulatory checkpoints, downstream inflammatory outputs, and their relevance to pulpal disease progression.

Dental pulp cells express functional inflammasome sensors, including NLRP3, AIM2, and NLRP6, which respond to inflammatory, metabolic, and damage-associated signals. Inflammasome activation follows a stepwise process of transcriptional priming and threshold-dependent assembly. While NF-κB- and type I interferon-mediated priming is adaptive and potentially reversible, ASC speck formation represents a molecular commitment point leading to caspase-1 activation, gasdermin D cleavage, IL-1β/IL-18 maturation, and pyroptotic cell death. Mitochondrial dysfunction, cytosolic mtDNA release, sustained ion fluxes, P2X7 signalling, and loss of endogenous inhibitory regulators further amplify inflammasome activity, promoting self-sustaining inflammatory circuits and progressive tissue breakdown.

Pulpal inflammation should be understood not as a linear increase in microbial burden, but as a biological transition driven by inflammasome checkpoint failure. Irreversible ASC speck formation functions as a commitment switch that sustains caspase-1 activation, gasdermin D-mediated pyroptosis, and self-amplifying IL-1β/IL-18 signalling. Within the confined pulp environment, this feed-forward inflammatory circuitry promotes neurovascular dysregulation and severe pain, ultimately becoming uncoupled from the initiating insult and incompatible with tissue recovery. Recognising Inflammasome activation (ASC speck formation) as a point of no return may refine diagnostic paradigms and help redefine the biological limits of vital pulp therapy.