AUTHOR=Hou Huan-Tzu , Wu Meng-Hsing , Tsai Shaw-Jenq 
  
TITLE=Pathophysiological mechanisms and next-generation therapeutic opportunities in endometriosis
  
JOURNAL=Experimental Biology and Medicine
  
VOLUME=Volume 251 - 2026
  
YEAR=2026
  
URL=https://www.ebm-journal.org/journals/experimental-biology-and-medicine/articles/10.3389/ebm.2026.11348
  
DOI=10.3389/ebm.2026.11348
  
ISSN=1535-3699
  
ABSTRACT=Endometriosis is a chronic, inflammatory, and heterogeneous disease affecting approximately 10% of women of reproductive age and is a major cause of pelvic pain and infertility. Despite its substantial clinical burden, diagnosis is frequently delayed, and current hormonal and surgical treatments remain non-curative, with recurrence and variable treatment responses being common. These clinical challenges reflect the complex and multifactorial nature of endometriosis, in which hormonal dysregulation, immune dysfunction, hypoxic and metabolic adaptation, and vascular remodeling interact to drive ectopic lesion establishment, persistence, and progression. This review integrates current understanding of the molecular and cellular mechanisms underlying endometriosis pathogenesis. We discuss how enhanced adhesion and invasion facilitate lesion establishment, how dysregulated innate and adaptive immune responses impair the clearance of ectopic endometrial cells and sustain chronic inflammation, and how hypoxia-driven signaling and metabolic reprogramming promote lesion survival. We further examine the roles of aberrant steroid hormone signaling, angiogenesis, and lymphangiogenesis in lesion maintenance and progression, as well as how these interconnected processes contribute to lesion heterogeneity and treatment resistance. Finally, we highlight how emerging multi-omics approaches and patient-derived organoid and assembloid models may facilitate mechanistic validation, biomarker discovery, and therapeutic development. By connecting the mechanisms of lesion initiation and progression with current therapeutic limitations, this review provides a framework for developing more precise, mechanism-based diagnostic and therapeutic strategies.