Copper-Targeted Therapy in Experimental Endometriosis: Effects of Ammonium Tetrathiomolybdate on Markers of the Interconnected Processes of Inflammation, Innervation, and Fibrogenesis

Endometriosis (EDT) is a chronic, estrogen-dependent disease characterized by inflammation, fibrosis, pelvic pain, and infertility. Current therapies show limited long-term efficacy and adverse effects, underscoring the need for novel therapeutic approaches. Elevated copper (Cu) levels have been reported in both patients and animal models of EDT, making Cu chelation a promising strategy. This work aimed to evaluate the impact of ammonium tetrathiomolybdate (TM) on the expression of markers related to the interconnected processes of inflammation, innervation, and fibrogenesis in mice with induced EDT. Twenty-four female C57BL/6 mice were assigned to Sham, EDT, or EDT+TM groups. Treatment with TM began on postoperative day 15, with samples collected one month after EDT induction. Peritoneal fluid cytokines (TNF-α, IL-1β, IL-6, TGF-β1) were quantified by ELISA. Endometriotic-like lesions were examined for mRNA expression of cytokines, neurotrophins (<i>Ngf</i>, <i>Bdnf</i>, <i>Ngfr</i>), neural markers (<i>Uchl1</i>, <i>Gap43</i>), neuropeptides and nociceptive markers (<i>Tac1/Tacr1</i>, <i>Calca/Calcrl/Ramp1</i>, <i>Trpv1</i>), and fibrogenic markers (<i>Vim</i>, <i>Acta2</i>, <i>Col1a1</i>, <i>Fmod</i>) by RT-qPCR. Neurotrophin protein levels were measured by ELISA, and collagen content was assessed through Masson's staining. TM significantly modulated inflammatory, neural, nociceptive, and fibrogenic markers, reducing most of them along with collagen content. These findings suggest that TM could impact key pathological mechanisms involved in EDT.