Regenerative-system dysfunction in organ fibrosis: Maladaptive regeneration, fibrotic memory, and therapeutic reprogramming

Table 1 Mechanisms contributing to regenerative-system dysfunction in organ fibrosis

Module	Relevant compartment	Organ/model and direct evidence	Scoped evidence grade	Therapeutic implication and limit
Exhaustion and senescence	ATII cells; differentiated renal epithelia; hepatic stellate cells	Mouse ATII perturbation with human IPF observations; renal G2/M perturbation and post-obstructive senolytic treatment[17,19,20]. Stellate-cell senescence can limit liver fibrosis[22]	Strong for specified epithelial mechanisms; exhaustion is not established by senescence markers alone. Direction differs by cell type	Target harmful states selectively. Depletion is not rejuvenation; a pilot trial does not establish fibrosis reversal
Persistent maladaptive repair states	Transitional alveolar cells; proximal tubular cells; hepatic ductular/progenitor-associated cells	Lung transitional-state perturbation; renal stress perturbation; mouse ductular-reaction/Hedgehog experiments[26,27,47]	Strong in selected lung models; moderate, model-specific renal/liver causal support. Human state maps remain associative	Test maturation and functional recovery separately from disappearance of a marker
ECM/mechanotransduction	Fibroblasts; ATII cells; extracellular niche	Cultured lung fibroblast stiffness-switch assay; YAP/TAZ perturbation; murine alveolar tension model; human decellularized lung ECM conditioning[13,32-34]	Direct culture memory; strong selected mechanistic effects. Human in vivo memory and whole-organ restoration are unproven	Normalize harmful cues without assuming all ECM is detrimental or that mechanics alone restores tissue
Inflammatory conditioning	Macrophages and immune-epithelial niches	Conditioned macrophage/rechallenge-transfer experiments in HClO-induced mouse fibrosis; postviral lung niche perturbation[39,42]	Moderate, direct within named models; conditioning effects vary by endpoint. Macrophage NASH epigenomics is not a withdrawal test[43]	Distinguish harmful training, protective tolerance, and continuing niche stimulation
Metabolic/mitochondrial dysfunction	Alveolar and renal epithelia	Mouse/human-associated CD38 epithelial-aging work and renal ferroptotic-stress perturbation[21,47]	Moderate, organ-specific mechanistic support; metabolic-memory erasure remains emerging/unproven	Measure cell fitness and fibrosis separately from durable post-withdrawal state correction
Epigenetic stabilization	Systemic-sclerosis dermal fibroblasts; liver macrophages as a contrasting context	TGFB2 enhancer persistence/perturbation in patient-derived fibroblasts; macrophage chromatin remodeling during ongoing steatohepatitis[14,43]	Strong for the specified enhancer mechanism ex vivo; macrophage memory remains inferred. No generalized progenitor-memory grade	Test durable locus- and cell-specific correction; avoid equating altered chromatin with erased memory
Cross-organ state convergence	Distinct epithelial, immune, and stromal populations	Lung, human liver, and kidney state/niche analyses; functional experiments apply only to the modules actually tested[8,10,36,37]	Moderate for recurrent associations; emerging for a universal causal sequence	Use shared signatures for target nomination, followed by organ-specific perturbation

Grades apply to the named mechanism, model, cell type, and endpoint, not to an entire organ or therapeutic class. Directness, memory, reversibility, and clinical efficacy are separate judgments (“Review methodology and evidence appraisal”). ATII: Alveolar type II; IPF: Idiopathic pulmonary fibrosis; YAP/TAZ: Yes-associated protein/transcriptional coactivator with PDZ-binding motif; ECM: Extracellular matrix; HClO: Hypochlorous acid; NASH: Nonalcoholic steatohepatitis.