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

Table 2 Operational assessment of proposed fibrotic-memory layers

Layer/carrier	Organ/model and test actually performed	Directness and scoped grade	Reversibility and remaining test
Epigenetic/dermal fibroblasts	Systemic-sclerosis fibroblasts: Retained TGFB2 enhancer program and chromatin-directed perturbation[14]	Direct ex vivo; strong for this enhancer mechanism, not for all chromatin signatures	Molecular program is perturbable in the assay; durable human tissue reversal is not established
Mechanical/fibroblasts	Cultured lung myofibroblasts transferred from stiff to soft substrates[13]	Direct culture persistence; moderate for generalization beyond the model	Retention depends on exposure history and assay conditions. Clinical memory erasure is untested
Inflammatory/macrophages	Conditioning, subsequent challenge, and transfer in an HClO-induced mouse fibrosis model[39]	Direct, model-specific response modulation; moderate. BCG and low-dose LPS have different effects	Fibrosis-modifying responses are demonstrated; durable normalization of human immune states is not
Niche/ECM	Human decellularized IPF matrix conditions cultured fibroblasts; postviral mouse lung immune-epithelial niche is functionally perturbed[34,42]	Direct niche instruction/persistence in these settings; moderate. Continued niche exposure is not cell-autonomous memory	Require removal of residual stimuli, cross-transfer controls, and durable functional follow-up to establish autonomous retention
Metabolic/epithelial cells	Renal metabolic-state and ferroptotic-stress studies demonstrate injury-associated dysfunction, not the full withdrawal-retention-reversal sequence[46,47]	Inferred; emerging for metabolic memory	Direct metabolic-memory erasure is unproven; test after stress and treatment withdrawal
Epithelial state/renal or alveolar cells	Senescent renal epithelia persist after relief of obstruction; senolytic treatment improves fibrosis without epithelial-specific targeting[20]. KRT8-associated lung states are a distinct context[8,25]	Direct, moderate evidence for the post-obstructive senescent-state example; KRT8 cell-autonomous memory remains inferred	Depletion is not reprogramming of surviving cells. Durable maturation and organ recovery require separate demonstration
Stromal activation state/hepatic stellate cells	Lineage-traced stellate cells deactivate after experimental liver-injury withdrawal but retain enhanced reactivation potential[52]	Direct, moderate evidence for sensitized activation-state memory; its epigenetic mechanism is not established by this experiment alone	Partial deactivation is demonstrated; complete return to a naive state or durable therapeutic memory erasure is not

Operational criteria: Document antecedent exposure, a suitable resolution/rest interval, and separation from continuing injury. Direct support comes from withdrawal-associated persistence, altered re-exposure responses, or selective perturbation of an already retained state. Perturbation only during ongoing injury is not a memory test. Molecular correction, cell depletion, histological regression, and functional recovery are different outcomes. TGFB2: Transforming growth factor beta 2; HClO: Hypochlorous acid; BCG: Bacillus Calmette-Guérin; LPS: Lipopolysaccharide; ECM: Extracellular matrix; IPF: Idiopathic pulmonary fibrosis; KRT8: Keratin 8.