BPC157 drives angiogenesis through FBXO22-dependent stabilization of BACH1

The body-protective polypeptide BPC157 is a natural therapeutic agent that has demonstrated robust efficacy in promoting repair across multiple organ systems, indicating its significant clinical potential. However, its clinical translation has been substantially hindered by a lack of understanding of its precise molecular mechanisms of action. Given its prominent proangiogenic effects, deciphering the mechanistic basis of its vascular regenerative actions is critically important. To investigate the molecular pathway underlying the proangiogenic effects of BPC157, we employed a combination of molecular, biochemical, and cellular approaches. These include techniques to identify protein‒protein interactions, assess ubiquitination status, and evaluate key cellular functions. The specific role of the proline residue at position 3 of BPC157 was also experimentally validated. We revealed that intracellular BPC157 engages the E3 ubiquitin ligase adaptor protein FBXO22 through its proline residue at position 3. This interaction results in the formation of a protein complex that effectively suppresses the ubiquitination and subsequent proteasomal degradation of the transcription factor BACH1, leading to significant stabilization of BACH1 protein levels. The consequent accumulation of BACH1 was shown to enhance critical processes in vascular regeneration, namely, the proliferation and tube-forming capacity of vascular endothelial cells. This study establishes a novel and critical molecular mechanism for the pharmacological actions of BPC157, centered on the BPC157-FBXO22-BACH1 axis. These findings provide a solid mechanistic foundation for the future development of BPC157-based or sequential therapeutic agents targeted at enhancing vascular repair. Furthermore, this work offers robust scientific evidence that can inform improved strategies for the prevention and treatment of tissue injury.