Rutaecarpine Improves Hyperlipidemia‐Related Erectile Dysfunction in Rats by Inhibiting Macrophage M1 Polarization‐Induced Corpus Cavernosum Fibrosis

BACKGROUND: Hyperlipidemia-related erectile dysfunction (HLED) responds poorly to first-line treatments such as phosphodiesterase type 5 inhibitors (PDE5Is), emphasizing the need for alternative therapeutic strategies. Rutaecarpine (RUT), a bioactive alkaloid, exhibits significant anti-inflammatory and anti-fibrotic effects. However, its therapeutic potential and mechanisms in HLED remain unexplored. OBJECTIVES: To evaluate the therapeutic effects and underlying mechanisms of RUT on HLED in vivo and in vitro. METHODS: In vivo, 48 male Sprague-Dawley rats were allocated into four groups: control, HLED, HLED+RUT-LD (low dose), and HLED+RUT-HD (high dose). Hyperlipidemia was induced through a high-fat diet, and RUT was administered orally. Erectile function was assessed using cavernous manometry, followed by analysis of penile tissues. In vitro, NR8383s were treated with lipopolysaccharide to induce M1 polarization and co-cultured with corpus cavernosum fibroblasts (CCFBs) to evaluate the impact of RUT on inflammation and fibrosis. RESULTS: RUT treatment partially improved erectile function in HLED rats. RUT reduced macrophage M1 polarization and fibrosis in penile tissues. In vitro, RUT inhibited LPS-induced M1 macrophage polarization and reduced fibrosis-related phenotype in co-cultured CCFBs. CONCLUSION: RUT could enhance erectile function in HLED rats by inhibiting macrophage M1 polarization and associated corpus cavernosum fibrosis. This study suggested that RUT could be a promising drug for treating HLED.