HMGA1, or High Mobility Group A1, is a nonhistone chromatin structural protein with no transcriptional activity. It mainly regulates genes by modifying DNA structure, playing a role in multiple pathways such as Wnt/β-catenin, PI3K/Akt, Hippo and MEK/ERK. HMGA1 is rare in adult cells but increases in highly proliferative cells like embryos. It is involved in numerous biological processes including embryonic development, cancer, and cellular senescence [3,5,7]. Genetic models, especially knockout (KO) and conditional knockout (CKO) mouse models, are valuable for studying HMGA1's functions.

In sepsis-induced cardiomyopathy (SIC), HMGA1 overexpression in cardiomyocytes aggravated cardiac dysfunction, inflammation, and apoptosis, while knockdown in H9c2 cardiomyocytes attenuated inflammation but aggravated apoptosis [1]. In pancreatic ductal adenocarcinomas (PDAC), HMGA1 deficiency disrupted oncogenic properties in vitro and impaired tumor inception and progression in KPC mice, revealing its role in driving pancreatic carcinogenesis and stroma formation [2]. In esophageal squamous cell carcinoma (ESCC), inhibition of HMGA1 enhanced sensitivity to ferroptosis and restored sensitivity to cisplatin in syngeneic allograft tumor models and genetically engineered mice, highlighting its role in chemoresistance [4]. In colorectal cancer, conditional knockout (Hmga1△IEC) and knock-in (Hmga1IEC-OE/+) mouse models demonstrated that HMGA1 promotes CRC progression by driving lipid synthesis [6]. In ESCC, conditional knockout of HMGA1 in mice reduced 4-nitroquinoline-1-oxide (4NQO)-induced esophageal tumorigenesis, indicating its role in promoting ESCC development by upregulating the pentose phosphate pathway [8].

In conclusion, HMGA1 is a crucial regulator in multiple biological processes and disease conditions. KO and CKO mouse models have been instrumental in revealing its role in various diseases, including SIC, PDAC, ESCC, and colorectal cancer. These models help us understand how HMGA1 contributes to disease development, offering potential therapeutic targets for these diseases.