SIMC1 (SUMO interacting motifs containing 1) is a multifunctional regulatory protein that primarily functions as an inhibitor of calpain-3 (CAPN3) protease activity and as a key regulatory component of the SMC5/6 complex. At the molecular level, SIMC1 suppresses CAPN3's rapid autolytic activity, acting as a dynamic molecular interaction regulator that allows CAPN3 to perform diverse cellular functions in skeletal muscle 1. SIMC1 also functions as a regulatory scaffold that can recruit CAPN3 substrates, such as CTBP1, enabling context-dependent shifting between protease inhibition and substrate recruitment 1. Additionally, SIMC1 serves as a specialized regulatory subcomplex (SIMC1-SLF2) that directs SMC5/6 to extrachromosomal DNA (ecDNA), recruiting SMC5/6 to SV40 large T antigen foci in PML nuclear bodies and mediating transcriptional repression of plasmid DNA through SUMO pathway-dependent mechanisms 23. Unlike the alternative SLF1/2 subcomplex, SIMC1-SLF2 does not participate in SMC5/6 recruitment to chr5 DNA lesions, indicating specialized roles for distinct regulatory subcomplexes 23. Clinically, SIMC1 downregulation is associated with endometrial carcinoma prognosis, appearing in a 17-gene signature predictive of overall survival in EC patients 4.