p16 Beyond Senescence: Cancer Biology Lessons Applied to Endometriosis

Area of Science:

• Reproductive biology and immunology
• Cellular and molecular medicine
• Gynaecological pathology

Background:

• Endometriosis is an estrogen-dependent condition causing pelvic pain and infertility, marked by chronic inflammation and fibrosis.
• Dysregulated expression of p16INK4a, a cellular senescence marker, is observed in endometriotic lesions, but its role is unclear.
• p16 normally suppresses proliferation, yet its altered expression in endometriosis is paradoxically linked to disease persistence.

Purpose of the Study:

• To clarify the context-dependent roles of p16 in endometriosis.
• To explore the relationship between p16, cellular senescence, the senescence-associated secretory phenotype (SASP), and the immune microenvironment.
• To propose a framework for therapeutic modulation targeting p16 pathways.

Main Methods:

• A narrative review of basic and clinical studies was conducted.
• Literature search focused on endometriosis, endometrial biology, cellular senescence, p16, SASP, immune regulation, and senotherapeutics.
• Analysis synthesized findings on p16 expression levels and their association with disease characteristics.

Main Results:

• Endometriotic lesions contain cell populations with both high and low p16 expression.
• Elevated p16 correlates with senescence, inflammation, an immunosuppressive microenvironment, and aberrant tissue remodeling.
• Reduced p16 may enhance proliferative capacity and cell survival, potentially via CDK4/6 activity and reduced SASP dependence.

Conclusions:

• p16 acts as a context-dependent regulator linking cellular senescence, inflammation, and tissue plasticity in endometriosis.
• Targeting mechanistic target of rapamycin (mTOR) signaling may reduce p16/p21 expression and SASP.
• Therapeutic strategies should focus on suppressing senescence and restoring a functional endometrial environment, rather than solely regulating p16.