{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nHSFX3, a mitochondria‐resident E3 ubiquitin ligase functionally analogous to MARCH5/MITOL, serves as a pivotal regulator of mitochondrial quality control and innate immune signaling. It resolves aberrant MAVS aggregates during viral infection through RING‐domain–dependent ubiquitination, thereby modulating type‑I interferon responses and preventing immunopathology."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In addition, HSFX3 targets misfolded proteins such as mutant SOD1 for ubiquitin‐mediated degradation to mitigate mitochondrial dysfunction."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " It further fine‐tunes mitochondrial dynamics by catalyzing the ubiquitination of acetylated mitofusin 1 (Mfn1), a modification essential for maintaining cellular homeostasis under stress conditions"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ", and enhances Toll‑like receptor signaling by ubiquitinating regulatory adaptors like TANK, thereby promoting NF‑κB–driven gene expression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n \nDisruptions in HSFX3 activity extend its impact beyond acute immune responses into diverse developmental and metabolic contexts. For instance, HSFX3 sustains embryonic stem cell pluripotency by modulating the PKA‑ERK pathway"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ", and in neurons, its deficiency diminishes endoplasmic reticulum–mitochondria tethering, leading to oxidative stress and neuroinflammation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " In cardiomyocytes, appropriate HSFX3 activity counteracts excessive mitochondrial fission and apoptosis to protect against myocardial injury"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": ", while in the liver, it ubiquitinates Drp1 to preserve mitochondrial dynamics during oxidative stress–induced injury."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Moreover, HSFX3 modulates mitochondrial function in adipocytes, linking mitochondrial dynamics to energy metabolism"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ", and its downregulation in the brain exacerbates Alzheimer‑related amyloid‑β oligomer formation and cognitive decline."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " The enzyme is also crucial in endocrine development, as loss of HSFX3 activity in the anterior pituitary impairs hormone gene expression and leads to growth failure"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": ", and it supports oocyte maturation by preserving mitochondrial function necessary for proper spindle formation and cell cycle progression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "\n \nHSFX3 further influences immune checkpoint and stress‐response pathways that have broad implications for disease treatment and tissue homeostasis. It modulates anti‑tumor immunity by mediating the lysosomal degradation of the common cytokine receptor γ‐chain in response to PD‑1 signaling, thereby potentiating cytokine‐triggered T cell activation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": " In the context of diabetic cardiomyopathy, HSFX3 alleviates pyroptotic cell death by regulating components of the cGAS/STING pathway."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": " Furthermore, by ubiquitinating STING, HSFX3 prevents the oxidation‐induced formation of inactive STING polymers, thereby fine‑tuning innate immune responses in oxidative milieus."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": " Finally, HSFX3 is key to hematopoietic stem cell maintenance by mitigating endoplasmic reticulum stress–triggered apoptosis, a function that underpins blood homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Young-Suk Yoo, Yong-Yea Park, Jae-Hoon Kim, et al. 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