Metabolic reprogramming by microvesicle restores glycolysis and rescues nerve injury-induced erectile dysfunction via endogenous S1P-mediated MEK/ERK signaling

  • Biomater Adv. 2026 Oct:187:214950. doi: 10.1016/j.bioadv.2026.214950.
Zhenkang Liang  1 ,  Zehong Chen  1 ,  Yuxuan Zhang  1 ,  Chaowei Zhang  1 ,  Kangping Sun  1 ,  Weipeng Zhang  1 ,  Cui Chen  2 ,  Wende Yang  1 ,  Hongbo Wei  3
Affiliations
  • 1. Department of Gastrointestinal Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Tianhe Road 600, Guangzhou, 510630, China.
  • 2. Department of Gastrointestinal Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Tianhe Road 600, Guangzhou, 510630, China; Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, Guangdong Province, China.
  • 3. Department of Gastrointestinal Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Tianhe Road 600, Guangzhou, 510630, China. Electronic address: [email protected].
PMID: 42184709 DOI: 10.1016/j.bioadv.2026.214950
Abstract

Cavernous nerve injury-induced erectile dysfunction (CNI-ED) lacks therapies that directly promote nerve regeneration. Here, we show that microvesicle (MV) derived from well differentiated PC12 cells restore erectile function in a rat CNI model by reprogramming local energy metabolism. Local administration of MV to the injured nerve elevated ATP levels, reduced neuronal Apoptosis and increased intracavernous pressure. Mechanistically, MV were enriched in sphingosine-1-phosphate (S1P), which activated S1PR1 and downstream MEK1/2-ERK1/2 signaling, leading to upregulation of glycolytic Enzymes (GLUT3, HK2, MCT4, LDHA) and enhanced glycolytic flux. Knockdown of SphK1 in donor cells depleted S1P from MV and abolished both metabolic and regenerative effects. Our data identify an S1P-S1PR1-MEK/ERK-glycolysis axis that drives nerve regeneration and nominate neuron-derived MV as a metabolism-targeted therapeutic strategy for CNI-ED.

Keywords
Cavernous nerve injury-induced erectile dysfunction; Glycolysis; Microvesicle; Nerve repair; Sphingosine-1-phosphate.
Products