Endometriosis is traditionally conceptualized as a pelvic lesion–centered disease; however, mounting evidence indicates it is a chronic, systemic, and multifactorial inflammatory disorder. This review examines the molecular dialog between ectopic endometrial tissue, the immune system, and peripheral organs, highlighting mechanisms that underlie disease chronicity, symptom variability, and therapeutic resistance. Ectopic endometrium exhibits distinct transcriptomic and epigenetic signatures, disrupted hormonal signaling, and a pro-inflammatory microenvironment characterized by inflammatory mediators, prostaglandins, and matrix metalloproteinases. Immune-endometrial crosstalk fosters immune evasion through altered cytokine profiles, extracellular vesicles, immune checkpoint molecules, and immunomodulatory microRNAs, enabling lesion persistence. Beyond the pelvis, systemic low-grade inflammation, circulating cytokines, and microRNAs reflect a molecular spillover that contributes to chronic pain, fatigue, hypothalamic–pituitary–adrenal axis dysregulation, and emerging gut–endometrium interactions. Furthermore, circulating biomarkers—including microRNAs, lncRNAs, extracellular vesicles, and proteomic signatures—offer potential for early diagnosis, patient stratification, and monitoring of therapeutic responses. Conventional hormonal therapies demonstrate limited efficacy, whereas novel molecular targets and delivery systems, including angiogenesis inhibitors, immune modulators, epigenetic regulators, and nanotherapeutics, show promise for precision intervention. A systems medicine framework, integrating multi-omics analyses and network-based approaches, supports reconceptualizing endometriosis as a systemic inflammatory condition with gynecologic manifestations. This perspective emphasizes the need for interdisciplinary collaboration to advance diagnostics, therapeutics, and individualized patient care, ultimately moving beyond a lesion-centered paradigm toward a molecularly informed, holistic understanding of endometriosis.
