Adaptive Regenerative Error Due to Loss of Cellular Reference Pattern: A Hypothesis of Dominant Substitution in Chronic Inflammatory Microenvironments

Aberrant cellular adaptation is a hallmark of various chronic diseases, including endometriosis, metaplasia, and fibrotic conditions. This paper proposes a novel hypothesis: that such pathological transformations result from a progressive loss of the original cellular reference pattern under sustained inflammatory and dysregulated conditions. Termed the Dominant Substitution Hypothesis, this model suggests that chronic microenvironmental disruption alters regenerative cues, gradually replacing healthy cell phenotypes with adaptive, yet functionally impaired, variants. Once a critical threshold is reached, the adaptive phenotype becomes dominant, perpetuating dysfunction and inhibiting restoration. The hypothesis integrates evidence from tissue plasticity, extracellular matrix disorganization, epigenetic modulation, microbiota-driven signaling, and immune-hormonal imbalance. Implications for diagnosis, prevention, and regenerative therapy are discussed, with a focus on early intervention to preserve cellular identity and interrupt the degenerative cycle.