{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSqualene epoxidase (SQLE) is a pivotal enzyme in cholesterol biosynthesis that catalyzes the oxidation of squalene to 2,3‑oxidosqualene, a critical, rate‐limiting step in the mevalonate pathway. Its expression is tightly regulated at multiple levels – at the transcriptional stage via sterol‐responsive elements (as shown by promoter analyses ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "], ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "]) and post‑translationally through cholesterol‐dependent degradation mechanisms. Such degradation is mediated by endoplasmic reticulum–associated ubiquitin ligases including MARCH6 ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "] and requires components of the ER quality control machinery – for example, studies have detailed the role of VCP and defined critical ubiquitination sites ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "]. Structural and functional dissection of its N‑terminal regulatory domain has revealed that squalene itself binds to this region to promote a feedforward response ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "], and the identification of truncated, constitutively active SQLE forms (which evade cholesterol‑mediated feedback) adds further nuance to its regulation ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "]. Moreover, alterations in upstream regulatory pathways – including those involving AMPK ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "] – and detailed biophysical studies delineating membrane topology ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "] underscore SQLE’s central role in maintaining cellular cholesterol homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_f", "ref": "3"}, {"type": "fg_f", "ref": "10"}, {"type": "fg_f", "ref": "2"}, {"type": "fg_f", "ref": "6"}, {"type": "fg_f", "ref": "4"}, {"type": "fg_f", "ref": "9"}, {"type": "fg_f", "ref": "5"}, {"type": "fg_f", "ref": "11"}, {"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its central metabolic role, aberrant SQLE expression and dysregulation have emerged as critical drivers of oncogenesis in a broad spectrum of human cancers. Elevated SQLE levels have been documented in lung squamous cell carcinomas ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "], breast cancers ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": "], prostate tumors ["}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "16", "end_ref": "18"}]}, {"type": "t", "text": "], hepatocellular carcinoma ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": "], colorectal cancers ["}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "20", "end_ref": "22"}]}, {"type": "t", "text": "], pancreatic adenocarcinomas ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "23"}]}, {"type": "t", "text": "], and glioblastomas ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "25"}]}, {"type": "t", "text": "]. In these contexts, SQLE fosters tumor cell proliferation, migration, invasion, and resistance to chemotherapeutic agents by modulating critical signaling cascades such as ERK and PI3K/Akt, and by influencing ferroptosis regulatory pathways. Comprehensive reviews further support its classification as a bona fide metabolic oncogene and underscore its utility as a prognostic marker and potential target for therapeutic intervention [."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "26", "end_ref": "32"}]}, {"type": "t", "text": " In addition, studies in endothelial cells have highlighted a role for the MARCH6–SQLE axis in angiogenesis ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "33"}]}, {"type": "t", "text": "], further broadening the oncogenic landscape associated with SQLE dysregulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}, {"type": "fg_f", "ref": "14"}, {"type": "fg_f", "ref": "19"}, {"type": "fg_f", "ref": "34"}, {"type": "fg_f", "ref": "16"}, {"type": "fg_f", "ref": "26"}, {"type": "fg_f", "ref": "13"}, {"type": "fg_f", "ref": "20"}, {"type": "fg_f", "ref": "17"}, {"type": "fg_f", "ref": "15"}, {"type": "fg_f", "ref": "21"}, {"type": "fg_fs", "start_ref": "23", "end_ref": "25"}, {"type": "fg_f", "ref": "27"}, {"type": "fg_f", "ref": "18"}, {"type": "fg_fs", "start_ref": "29", "end_ref": "31"}, {"type": "fg_f", "ref": "22"}, {"type": "fg_f", "ref": "32"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its roles in human metabolism and oncogenesis, point mutations in SQLE have been identified as the causative factor behind resistance to the antifungal agent terbinafine in dermatophytes ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "35"}]}, {"type": "t", "text": "]. These findings underscore the enzyme’s clinical relevance not only as a metabolic and oncogenic driver but also as a therapeutic target across a range of diseases. The emerging body of literature highlights both the potential for selective SQLE inhibition in cancer treatment and the necessity of understanding its regulation to overcome challenges such as drug resistance."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "35"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Masaaki Nagai, Jun Sakakibara, Yuichi Nakamura, et al. 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