Acoustic reprogramming of macrophages by low-intensity pulsed ultrasound alleviates endometrial fibrosis with involvement of the SOCS3/JAK1/STAT3 axis.

AIMS: Dysregulated macrophage polarization and persistent inflammation drive post-injury endometrial fibrosis and intrauterine adhesion (IUA), yet non-invasive early strategies remain limited. This study investigated the therapeutic effects and mechanisms of low-intensity pulsed ultrasound (LIPUS)-induced macrophage reprogramming in alleviating endometrial fibrosis and restoring fertility. MATERIALS AND METHODS: Immunoregulatory and anti-fibrotic effects of LIPUS were evaluated by optical coherence tomography, flow cytometry, immunohistochemistry, and immunofluorescence. Integrative transcriptomics of LIPUS-treated tissues and macrophages identified key targets and pathways. Western blotting and RT-qPCR assessed SOCS3/JAK1/STAT3 axis changes. Macrophage-endometrial stromal cell crosstalk was examined via co-culture, and pathway dysregulation was further evaluated in patient tissues. KEY FINDINGS: LIPUS suppresses M1 macrophage polarization and alleviates endometrial fibrosis in a mice model of chemically induced endometrial injury. Integrative transcriptomics identified SOCS3 as a significantly differentially expressed gene upregulated by LIPUS. Validation experiments confirmed that LIPUS upregulates SOCS3 with concomitant JAK1-STAT3 and inhibits pathological M1, while attenuating paracrine-driven transdifferentiation of endometrial stromal cells into myofibroblasts via suppression of the TGF-β/Smad3 cascade. Pharmacological JAK1 inhibition recapitulated LIPUS effects, whereas IL-6 pretreatment partially abrogated them, supporting the involvement of the SOCS3/JAK1/STAT3 pathway. LIPUS also helped ameliorate endometrial structural remodeling and restores fertility. SOCS3 downregulation and STAT3 hyperactivation were confirmed in fibrotic endometrial tissues from patients, supporting the clinical relevance of this pathway as a therapeutic target. SIGNIFICANCE: The study demonstrates that LIPUS reprograms macrophages with involvement of the SOCS3/JAK1/STAT3 axis in association with alleviation of endometrial fibrosis and improve function, offering a potential non-invasive early intervention for IUA.