{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Acid ceramidase, encoded by the ASAH1 gene, is a lysosomal enzyme that catalyzes the hydrolysis of ceramide into sphingosine, thereby playing a central role in regulating sphingolipid metabolism and the balance between pro‐apoptotic ceramide and pro‐survival sphingosine (and its phosphorylated derivative, sphingosine‐1‐phosphate). This enzymatic activity is critical for maintaining cellular homeostasis in diverse biological settings. For example, proper ASAH1 function is essential for normal brain and systemic development, as complete loss of acid ceramidase activity in mice results in early embryonic lethality, while partial loss-of-function mutations in ASAH1 in humans are associated with a spectrum of neurological disorders such as spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) and Farber disease."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition to its canonical role in ceramide catabolism, biochemical studies have demonstrated that acid ceramidase can also operate in the reverse direction by promoting ceramide synthesis under certain conditions, highlighting its bidirectional function in modulating sphingolipid levels."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Dysregulation or overexpression of ASAH1 has important pathophysiological consequences. Elevated acid ceramidase activity has been linked to cancer progression and therapeutic resistance—by lowering ceramide accumulation, tumor cells may evade ceramide-induced apoptosis and promote proliferative, migratory, and drug-resistant phenotypes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Conversely, inhibition or down-regulation of ASAH1 can lead to ceramide buildup, thereby sensitizing cells to apoptotic stimuli and enhancing the efficacy of antitumor therapies.\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its roles in development and cancer, ASAH1-mediated ceramide metabolism contributes to tissue-specific functions such as the modulation of neuronal survival in mood disorders and the regulation of skin barrier homeostasis, where alterations in ceramide levels affect cellular stress responses and tissue repair."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In summary, ASAH1 is a pivotal regulator of sphingolipid metabolism whose activity influences cell fate decisions, tissue homeostasis, and disease pathogenesis across a broad spectrum of conditions—including neurological disorders, cancer, and skin diseases—thereby emerging as a promising candidate for targeted therapeutic intervention."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Chi-Ming Li, Jae-Ho Park, Calogera M Simonaro, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Insertional mutagenesis of the mouse acid ceramidase gene leads to early embryonic lethality in homozygotes and progressive lipid storage disease in heterozygotes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genomics (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1006/geno.2002.6686"}], "href": "https://doi.org/10.1006/geno.2002.6686"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11829492"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11829492"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Jie Zhou, Marcel Tawk, Francesco Danilo Tiziano, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Spinal muscular atrophy associated with progressive myoclonic epilepsy is caused by mutations in ASAH1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ajhg.2012.05.001"}], "href": "https://doi.org/10.1016/j.ajhg.2012.05.001"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22703880"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22703880"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Nozomu Okino, Xingxuan He, Shimon Gatt, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The reverse activity of human acid ceramidase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M303310200"}], "href": "https://doi.org/10.1074/jbc.M303310200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12764132"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12764132"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Xingxuan He, Nozomu Okino, Rajwinder Dhami, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Purification and characterization of recombinant, human acid ceramidase. Catalytic reactions and interactions with acid sphingomyelinase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M301936200"}], "href": "https://doi.org/10.1074/jbc.M301936200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12815059"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12815059"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Antonio F Saad, William D Meacham, Aiping Bai, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The functional effects of acid ceramidase overexpression in prostate cancer progression and resistance to chemotherapy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Biol Ther (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4161/cbt.6.9.4623"}], "href": "https://doi.org/10.4161/cbt.6.9.4623"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17881906"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17881906"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Eugen Ruckhäberle, Achim Rody, Knut Engels, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Microarray analysis of altered sphingolipid metabolism reveals prognostic significance of sphingosine kinase 1 in breast cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Breast Cancer Res Treat (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10549-007-9836-9"}], "href": "https://doi.org/10.1007/s10549-007-9836-9"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18058224"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18058224"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Erich Gulbins, Monica Palmada, Martin Reichel, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Acid sphingomyelinase-ceramide system mediates effects of antidepressant drugs."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Med (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nm.3214"}], "href": "https://doi.org/10.1038/nm.3214"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23770692"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23770692"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Yutaka Hatano, Hiroto Terashi, Shoko Arakawa, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Interleukin-4 suppresses the enhancement of ceramide synthesis and cutaneous permeability barrier functions induced by tumor necrosis factor-alpha and interferon-gamma in human epidermis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Invest Dermatol (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.0022-202X.2005.23651.x"}], "href": "https://doi.org/10.1111/j.0022-202X.2005.23651.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15816837"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15816837"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Carmen Bedia, Josefina Casas, Nathalie Andrieu-Abadie, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Acid ceramidase expression modulates the sensitivity of A375 melanoma cells to dacarbazine."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M110.216382"}], "href": "https://doi.org/10.1074/jbc.M110.216382"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21700700"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21700700"}]}]}]}