Sesn1, also known as PA26, is a stress-inducible protein involved in multiple biological functions. It plays a crucial role in pathways such as Toll-like receptor signaling, innate immune regulation, and is associated with important biological processes like cell proliferation, apoptosis, and aging. Genetic models are valuable for studying Sesn1 as they can help uncover its function in various physiological and pathological conditions [2,3,4].

In skeletal muscle, knockdown of Sesn1 mimicked the ageing phenotypes seen in FOXO3-deficient human myotubes, while its genetic activation alleviated senescence. Recombinant Sesn1 protein attenuated myotube senescence in vitro and facilitated muscle regeneration in vivo, indicating its role in counteracting skeletal muscle ageing [1].

In neuroblastoma, knockdown of Sesn1 promoted cell proliferation, migration, and invasion, and shortened the survival time of tumor-bearing mice, suggesting it functions as a tumor suppressor gene via the Toll-like receptor signaling pathway [2].

In innate immunity, Sesn1-deficient mice exhibited stronger ability against HSV-1 infection. The replenishment of Sesn1 effectively inhibited IFN-I production and autoimmune responses in SLE specimens and trex1 KO mouse models, as Sesn1 targeted STING1 and promoted its autophagic degradation [3].

In head and neck squamous cell carcinoma (HNSCC), Sesn1 overexpression inhibited cell proliferation, migration, and invasion. Low Sesn1 expression was positively correlated with poor prognosis, and miR-377-3p negatively regulated Sesn1 [4].

In human umbilical vein endothelial cells (HUVECs) stimulated by oxidized low-density lipoprotein (Ox-LDL), Sesn1 overexpression suppressed inflammation, apoptosis, and endothelial-mesenchymal transition (EndMT) by regulating AMPK/SIRT1/LOX1 signaling [5].

In atherosclerosis models, overexpression of Sesn1 in ApoE-/-mice inhibited plaque formation, endothelial injury, inflammatory response, oxidative stress, and endothelial ferroptosis, potentially through activation of P21 [6].

In conclusion, Sesn1 has diverse essential biological functions. Model-based research, especially through gene knockout mouse models, has revealed its significance in areas such as muscle ageing, tumorigenesis, innate immune homeostasis, and endothelial-related disorders. These findings provide potential diagnostic biomarkers and intervention strategies for related diseases.