{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSREBF2 is a central transcription factor regulating cholesterol homeostasis by activating a network of genes involved in de novo cholesterol biosynthesis, uptake, and modification. Its canonical functions include promoting expression of key enzymes such as HMG‐CoA reductase, LDL receptor and sterol‐modifying enzymes, as well as regulating PCSK9 transcription. Notably, the primary SREBF2 transcript harbors the intronic microRNA miR‑33, which acts in concert with SREBF2 to curtail cholesterol efflux via posttranscriptional repression of transporters (e.g., ABCA1 and ABCG1) and to modulate fatty acid oxidation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "10"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nSREBF2 activity is exquisitely regulated by intracellular cholesterol levels and diverse stress signals. In the endoplasmic reticulum, cholesterol binding to SCAP establishes a cooperative threshold that governs SREBF2 transport and activation, while post‐translational modifications—such as ERK‐mediated phosphorylation that prevents inhibitory sumoylation—enhance its transcriptional potency. Crosstalk with pathways involving ATF6, TRC8 and AMPK (including modulation by TSH) couples SREBF2 processing to nutritional status, ER stress and inflammatory signals. Moreover, mTORC1 signaling and mechanical cues can further influence its trafficking and cleavage, ensuring that SREBF2 activity is tightly integrated with the cell’s metabolic and environmental state. Oxidative stress and disturbed flow similarly engage SREBF2 to trigger changes in gene expression within vascular endothelium."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}, {"type": "fg_f", "ref": "4"}, {"type": "fg_f", "ref": "12"}, {"type": "fg_f", "ref": "3"}, {"type": "fg_fs", "start_ref": "14", "end_ref": "17"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn pathophysiological contexts, aberrant SREBF2 activation contributes to metabolic dysregulation, cancer progression and inflammatory responses. In tumors, oncogenic signals (e.g. via PI3K/mTORC1 pathways and acidic extracellular pH) promote SREBF2‐driven lipogenesis that supports cell proliferation, cancer stemness and metastasis; targeting SREBF2 (or its regulators) has shown promise in overcoming chemoresistance. In muscle and other tissues, stress‐induced SREBF2 activation facilitates membrane remodeling and may be modulated by epigenetic changes, linking its expression to dyslipidemia. Furthermore, by interfacing with components such as the NLRP3 inflammasome and inflammatory microRNAs, SREBF2 bridges metabolic control and innate immunity—a role highlighted in cardiovascular and infectious diseases (including severe COVID‑19). These multifaceted functions underscore the therapeutic potential of modulating SREBF2 and its regulatory network in diverse disease settings."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "18", "end_ref": "33"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Koichi Misawa, Taro Horiba, Naoto Arimura, et al. 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