Heterotopic ossification (HO) is a pathological process in which bone forms in soft tissues. It can be classified into genetic HO (e.g., fibrodysplasia ossificans progressiva, FOP) and traumatic HO (tHO). NF-κB signaling plays a critical role in HO by driving inflammation, modulating chondrogenesis, and promoting osteogenesis. In tHO, NF-κB signaling is involved in the initial inflammation stage, where it interacts with SIRT1, AMPK, and the NLRP3 inflammasome to regulate inflammatory responses. In FOP, mutated ACVR1-induced NF-κB signaling exacerbates inflammation and promotes chondrogenesis and osteogenesis in mesenchymal stem cells (MSCs) through interactions with Smad and mTOR signaling. NF-κB signaling is also involved in the chondrogenesis and osteogenesis stages, where it interacts with pathways such as PI3K/AKT, mTOR, and BMP to regulate cell differentiation and bone formation. SIRT1 and AMPK can inhibit NF-κB signaling, while dysregulation of these pathways contributes to inflammatory responses in HO. The NLRP3 inflammasome is involved in pyroptosis and the secretion of inflammatory cytokines, which can promote HO. NF-κB signaling also mediates interactions between macrophages and MSCs, influencing chondrogenesis and osteogenesis. BMP signaling is crucial for bone development and is involved in HO progression. NF-κB signaling can regulate BMP signaling, which is essential for chondrogenesis and osteogenesis. Additionally, mechanical stress can activate mTOR and NF-κB signaling, promoting osteoblast differentiation and HO. SPARC plays a role in osteoblast differentiation and bone formation, and its expression is increased in HO. Overall, NF-κB signaling is a key regulator of HO, and targeting this pathway may offer therapeutic strategies for HO treatment.Heterotopic ossification (HO) is a pathological process in which bone forms in soft tissues. It can be classified into genetic HO (e.g., fibrodysplasia ossificans progressiva, FOP) and traumatic HO (tHO). NF-κB signaling plays a critical role in HO by driving inflammation, modulating chondrogenesis, and promoting osteogenesis. In tHO, NF-κB signaling is involved in the initial inflammation stage, where it interacts with SIRT1, AMPK, and the NLRP3 inflammasome to regulate inflammatory responses. In FOP, mutated ACVR1-induced NF-κB signaling exacerbates inflammation and promotes chondrogenesis and osteogenesis in mesenchymal stem cells (MSCs) through interactions with Smad and mTOR signaling. NF-κB signaling is also involved in the chondrogenesis and osteogenesis stages, where it interacts with pathways such as PI3K/AKT, mTOR, and BMP to regulate cell differentiation and bone formation. SIRT1 and AMPK can inhibit NF-κB signaling, while dysregulation of these pathways contributes to inflammatory responses in HO. The NLRP3 inflammasome is involved in pyroptosis and the secretion of inflammatory cytokines, which can promote HO. NF-κB signaling also mediates interactions between macrophages and MSCs, influencing chondrogenesis and osteogenesis. BMP signaling is crucial for bone development and is involved in HO progression. NF-κB signaling can regulate BMP signaling, which is essential for chondrogenesis and osteogenesis. Additionally, mechanical stress can activate mTOR and NF-κB signaling, promoting osteoblast differentiation and HO. SPARC plays a role in osteoblast differentiation and bone formation, and its expression is increased in HO. Overall, NF-κB signaling is a key regulator of HO, and targeting this pathway may offer therapeutic strategies for HO treatment.