Unraveling the dual roles of MICAL2 in skeletal muscle physiology and fusion negative rhabdomyosarcoma tumor progression.

Rhabdomyosarcoma (RMS) is a prevalent soft tissue sarcoma in pediatric populations characterized by dysregulated myogenesis and limited treatment options. Notably, fusion negative RMS (FN-RMS) constitutes the predominant subtype in pediatric patients and commonly harbors RAS mutations, resulting in uncontrolled cell proliferation and invasion. To date, the precise molecular determinants underlying FN-RMS tumor biology remain poorly understood, but there is increasing evidence implicating aberrant cytoskeletal remodeling in promoting malignant phenotypes. In this study, we present MICAL2, a flavin monooxygenase involved in regulating actin dynamics, as a novel driver of FN-RMS tumor progression. We first revealed elevated MICAL2 expression in FN-RMS cell lines, which was consistent with prior reports in other malignancies, then demonstrated that its silencing altered tumor cell behaviors. By knocking down MICAL2 using RNA interference strategies, murine and human FN-RMS cells displayed reduced proliferative and migratory capacities in vitro, which translated to attenuated primary tumor growth, inhibited metastasis formation, and improved functional performances in vivo. Furthermore, multi-omics analyses highlighted the molecular changes associated with MICAL2 silencing, including simultaneous suppression of oncogenic programs and enhancement of muscle integrity and oxidative metabolic function. Collectively, these data highlight the duality of MICAL2 as a cytoskeletal regulator whose dysregulation may disrupt myogenic identity and promote FN-RMS pathogenesis.