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

Table 4 Classification and evidence status of therapeutic strategies

Approach/category	Organ, model, and target	Directly supported effect/evidence stage	What is not established/main limitation
Progenitor-state rejuvenation/reprogramming only if durable and controlled	Partial-reprogramming experiments in aging/progeroid mice and tissue-repair settings[53]	Preclinical improvement in selected age-associated cellular and tissue phenotypes	Not a general fibrosis trial, a validated memory-erasure assay, or established human progenitor rejuvenation
Epigenetic state correction/candidate direct reprogramming	Systemic-sclerosis dermal fibroblast enhancer perturbation[14]; Arid1a deletion in murine liver-fibrosis/regression models[63]	Direct locus-level mechanism ex vivo; preclinical liver-fibrosis reduction, including intervention after injury cessation	No established human antifibrotic efficacy or complete memory erasure; delivery, identity stability, and oncogenic risk require separate testing
Direct lineage conversion/reprogramming	Murine cardiac fibroblasts converted toward induced cardiomyocytes after injury[58]	Animal proof of lineage conversion and selected functional effects	Not reversal of established chronic human scar; efficiency, maturation, integration, and lineage control remain limiting
Senomorphics/state modulation; senolytics/cell depletion	Mouse pulmonary fibrosis, post-obstructive renal senescence, and an open-label human IPF pilot[15,20,23]	Preclinical benefit in specified endpoints; human pilot feasibility	Senolysis is not reprogramming; pilot data do not establish antifibrotic efficacy. Beneficial senescent states may be lost
ECM/mechanotransduction modulation/niche intervention	Cultured lung fibroblast stiffness-switch and YAP/TAZ perturbation models[13,32]	Direct effects on mechanical retention or activation in the particular assay; primarily preclinical	Matrix instruction is not cell-intrinsic memory; clinical restoration and optimal timing are unproven
Immune-state modulation/complementary unless durable resetting is shown	Macrophage conditioning in mouse systemic-sclerosis-like fibrosis[39]; IL-22 liver progenitor studies[64]	Conditioning changes selected fibrosis outcomes; IL-22 promotes progenitor expansion experimentally, with human associations	Opposing conditioning effects; IL-22 proliferation is not demonstrated fibrosis reversal. Infection and impaired repair require assessment
Metabolic correction/state modulation	CD38-related alveolar aging and renal ferroptotic-stress models[21,47]	Direct preclinical modification of specified stress/repair pathways and fibrosis-associated outcomes	No complete withdrawal-based metabolic-memory erasure; systemic and cell-specific effects need evaluation
Cell replacement/separate regenerative strategy	Tested cell products in chronically scarred rodent hearts[7]	Negative primary evidence: No rejuvenation in that chronic-scar setting	No class-wide efficacy inference; engraftment, maturation, host response, and disease stage must be tested for each product
Organoid-guided screening/research platform, not itself therapy	Human pluripotent-stem-cell-derived nephron organoids and expandable adult liver cultures[50,51]	Direct platform evidence for development/injury modeling and culture-based experimentation	Memory washout/rechallenge protocols are a proposed extension here; no direct patient effect from screening alone. Incomplete niche and model fidelity remain limitations

A mechanistic or model-specific result is not a clinical evidence grade. Reprogramming requires controlled and durable intrinsic state, identity, or trajectory correction. Depletion, transient pathway modulation, matrix correction, cell delivery, and screening are different categories. IPF: Idiopathic pulmonary fibrosis; ECM: Extracellular matrix; YAP/TAZ: Yes-associated protein/transcriptional coactivator with PDZ-binding motif; IL-22: Interleukin-22.