Background <p>Cavernous nerve injury (CNI) is a prominent etiological factor in the development of erectile dysfunction (ED). Nevertheless, the underlying pathophysiological mechanisms of CNI-induced ED (CNI-ED) are not fully elucidated. Galectin-3 (Gal-3), an indicator of inflammation and fibrosis, has been implicated in the pathogenesis of arteriogenic ED. In this study, we investigate the role of Gal-3 in CNI-ED and explore the potential mechanisms by which adipose-derived mesenchymal stem cell exosomes (ADSC-Exo) ameliorate CNI-ED.</p> Methods <p>We established a bilateral CNI (BCNI) rat model and evaluated erectile function using intracavernous pressure (ICP), mean arterial pressure (MAP), and infrared ray thermography (IRT). The expression level of Gal-3 was measured in the major pelvic ganglia (MPG), penile corpus cavernosum, and cultured cells, with its expression modulated by lentiviral vectors. A combination of experimental approaches, including western blot, immunofluorescence, and flow cytometry analysis, were employed to investigate the role of Gal-3 in the progression of CNI-ED. Additionally, the potential molecular mechanisms by which ADSC-Exo ameliorates CNI-ED were explored.</p> Results <p>Our findings indicated that the expression of Gal-3 is significantly upregulated in the MPG and penile corpus cavernosum of BCNI rats. This upregulation was accompanied by oxidative stress and activation of the TLR4/MyD88/NF-κB signaling pathway. Following lentiviral knockdown of Gal-3, erectile function in BCNI rats was improved. Moreover, ADSC-Exo transplantation inhibited Gal-3 expression and the related inflammatory profibrotic cascades.</p> Conclusions <p>Collectively, this study demonstrates that upregulation of Gal-3 promotes the pathogenesis of CNI-ED by triggering oxidative stress and inflammatory profibrotic cascades and highlights the therapeutic potential of ADSC-Exo in restoring erectile function via Gal-3 inhibition.</p> Graphical Abstract <p></p>