RARE DISEASE
Disorder of fatty acid oxidation and ketogenesis
Disorder of fatty acid oxidation and ketogenesis
Disorder of fatty acid oxidation and ketogenesis
Drug discovery
2
drugs
With orphan designations
Overview
Disorders of fatty acid oxidation and ketogenesis are inborn errors disrupting mitochondrial β-oxidation or carnitine-mediated transport, impairing energy production from fats [1][2]. Affected individuals experience hypoketotic hypoglycemia during catabolic stress, with risks of hepatic dysfunction, cardiomyopathy, rhabdomyolysis, and neurocognitive impairment [2][8]. These autosomal recessive conditions require lifelong management focused on metabolic stability and energy substrate optimization [2][16].
Burden
Acute crises cause life-threatening hypoglycemia, hepatic encephalopathy, or cardiac arrest [1][19]. Chronic complications include developmental delay, retinopathy (LCHAD), and cardiomyopathy [16][19]. Despite newborn screening, recurrent hospitalizations and neurocognitive deficits persist in 30–40% of cases [3][8].
Categories: rare genetic diseases, rare inborn errors of metabolism
Research Papers
197 drug discovery papers about Disorder of fatty acid oxidation and ketogenesis, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
197 drug discovery papers about Disorder of fatty acid oxidation and ketogenesis, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-07-24 | Progressive Weakness and Hypoglycemia in a Child With Selective Eating: A Nutritional Mimic of a Fatty Acid Oxidation Disorder.
Severe selective eating in children can lead to clinically important nutritional deficiencies. We report a 5-year-old boy with autism spectrum disorder who presented with progressive weakness and hypoglycemia mimicking a fatty acid oxidation disorder (FAOD). His diet had consisted almost exclusively of white rice, and he had developed clinically significant manifestations of folate and vitamin A deficiency before this presentation. After several months of progressive weakness, he developed a generalized seizure with severe hypoglycemia and blunted ketogenesis during an intercurrent infection. Laboratory testing showed low riboflavin, low free carnitine with an elevated acylcarnitine-to-free carnitine ratio, and mild C6-C10 acylcarnitine elevations. Nerve conduction studies suggested sensory-predominant axonal neuropathy. These findings resembled multiple acyl-CoA dehydrogenase deficiency, a FAOD. Riboflavin and levocarnitine supplementation was followed by recovery of independent walking, with no recurrence over 7 years. This case illustrates a nutritional mimic of FAODs and highlights the need for nutritional and metabolic evaluation in selectively eating children with progressive weakness or hypoglycemia.
2026-02-16 | The Keto–Inflammatory Network: From Systems Biology to Biological Code
The transition from energy sufficiency to deficiency triggers complex metabolic and immune adaptations that have traditionally been viewed through a reductionist pathological lens. During early lactation, coordinated mobilization of adipose tissue, muscle protein, and bone minerals supports milk synthesis, with ketogenesis specifically arising from hepatic oxidation of non–esterified fatty acids. This review introduces the Keto–Inflammatory Network (KIN), a novel framework positioning ketonemia as an evolutionarily conserved adaptive response rather than inherent metabolic dysfunction. The KIN integrates β–hydroxybutyrate (BHB) signaling with immune modulation, epigenetic regulation, circadian rhythms, and microbiota interactions. Through mechanisms including NLRP3 inflammasome inhibition, HDAC–mediated epigenetic modifications, and HCAR2 receptor activation, ketone bodies orchestrate anti–inflammatory responses while maintaining metabolic flexibility. Building upon important precedent work recognizing beneficial roles of ketones in ruminant metabolism, this review synthesizes recent advances in immunometabolism and systems biology into an integrated framework. The KIN encompasses calcium–ketone integration through the Calci–Keto–Inflammatory Code (CKIC), temporal regulation via the Ketoinflammatory Clock, and trans–kingdom signaling through microbiota interactions. In dairy cattle, this perspective reframes periparturient ketonemia as existing on a continuum from adaptive to pathological, with biological meaning determined by integrated metabolic–inflammatory patterns rather than absolute ketone concentrations. The CKIC paradigm, while requiring prospective validation, suggests novel therapeutic approaches leveraging ketone signaling for inflammatory diseases, autoimmune conditions, and metabolic disorders while challenging traditional threshold–based ketosis management strategies. This systems–level understanding opens new avenues for precision interventions that work with, rather than against, evolved adaptive mechanisms refined through millions of years of mammalian evolution. By distinguishing ketonemia (measurable ketone elevation) from pathological ketosis (dysregulated ketone accumulation), and by integrating evidence from both ruminant and monogastric models, this review provides a comprehensive framework for next–generation metabolic medicine.
2026-02-09 | Distinct effects of ketogenic and non-ketogenic weight-loss diets on hepatic steatosis and mitochondrial metabolism in MASLD.
Weight loss is the cornerstone of therapy for metabolic dysfunction-associated steatotic liver disease (MASLD). However, the optimal dietary approach for reducing intrahepatic triglycerides (IHTG) and the mechanisms underlying steatosis resolution remain poorly defined. We investigated whether weight loss via a ketogenic diet (KD) compared with a non-ketogenic diet (ND) differentially affects IHTG content, hepatic mitochondrial metabolism, and the circulating metabolome. Individuals with varying IHTG content underwent short-term hypocaloric KD and ND in a crossover design. Before and after each diet, IHTG was quantified by proton magnetic resonance spectroscopy and liver stiffness by magnetic resonance elastography. We used state-of-the-art isotope tracer methodology to compare in vivo rates of hepatic mitochondrial tricarboxylic acid (TCA) cycle oxidation, endogenous glucose production, and β-hydroxybutyrate production (ketogenesis). Targeted plasma metabolomics by NMR and LC-MS was used to evaluate systemic metabolic responses. Despite similar energy deficits and body fat loss, IHTG decreased 45% more with KD than ND (-29% vs. -20%), accompanied by a threefold greater improvement in hepatic insulin sensitivity (59% vs. 21%). KD, but not ND, markedly reduced serum insulin concentrations (-54%), thereby promoting lipolysis and intrahepatic fatty acid partitioning toward mitochondrial β-oxidation, increasing hepatic mitochondrial [NADH]/[NAD+] (redox state) (+51%), and decreasing rates of hepatic mitochondrial TCA cycle oxidation (-34%). KD, but not ND, increased plasma concentrations of branched-chain amino acids, acylcarnitines, and TCA cycle intermediates. Both diets ameliorated MASLD, but KD produced a greater reduction in IHTG owing to a starvation-like metabolic state. However, the benefits of KD were accompanied by increased hepatic mitochondrial redox state and suppression of TCA cycle oxidation, which are features previously linked to progressive liver injury. This study provides mechanistic justification for considering dietary composition, in addition to caloric restriction, as a key determinant of steatosis resolution in metabolic dysfunction-associated steatotic liver disease (MASLD). The findings highlight a potential trade-off between greater short-term reductions in liver fat and the emergence of metabolic features previously associated with increased susceptibility to liver injury. While a ketogenic diet may facilitate rapid liver fat reduction in selected clinical contexts, its use should be approached cautiously, particularly in individuals with advanced MASLD. These results underscore the need for systematic evaluation of dietary composition as a determinant of both efficacy and safety of nutritional interventions for MASLD. NCT03737071.
2025-07-01 | The Multifaceted Influence of Beta-Hydroxybutyrate on Autophagy, Mitochondrial Metabolism, and Epigenetic Regulation.
Beta-hydroxybutyrate (BHB), a key ketone body produced during fatty acid metabolism, plays critical roles in various physiological and pathological conditions. Synthesized in the liver through ketogenesis, BHB serves as an essential energy substrate during glucose deprivation, supporting survival by efficiently utilizing fat reserves. It crosses the blood-brain barrier, providing energy for neuronal function, enhancing cognitive processes such as learning and memory, and offering neuroprotection by modulating synaptic plasticity and neurotransmitter levels. BHB's impact extends to cellular pathways, including autophagy, mitochondrial biogenesis, and epigenetic regulation. By modulating autophagy, BHB ensures mitochondrial integrity and function through intricate molecular pathways involving AMPK, mTOR, PINK1/Parkin, and others. This regulation plays vital roles in neurodegenerative diseases, metabolic disorders, cancer, and cardiovascular diseases, reducing oxidative stress and preventing cellular dysfunction. Epigenetically, BHB acts as an endogenous histone deacetylase inhibitor, inducing beneficial histone modifications that enhance cellular resilience and stress responses. This epigenetic influence is crucial in conditions like diabetes and cancer, aiding insulin secretion, protecting pancreatic beta cells, and impacting cancer cell gene expression and survival. Furthermore, BHB's therapeutic potential is evident in its ability to improve mitochondrial function across various tissues, including neurons, muscle, and liver. By enhancing mitochondrial respiration, reducing oxidative stress, and altering metabolic pathways, BHB mitigates conditions such as ICU-acquired weakness, nonalcoholic fatty liver disease, and cardiovascular diseases. BHB's modulation of autophagy and epigenetic regulation underscores its comprehensive role in cellular homeostasis and health across multiple physiological contexts, providing a foundation for future therapeutic strategies.
2024-11-21 | Identification of chikusetsusaponin IVa as a novel lysine-specific demethylase 1 inhibitor that ameliorates high fat diet-induced MASLD in mice.
Diet-induced metabolic dysfunction steatotic liver disease (MASLD) is also called as non-alcoholic fatty liver disease (NAFLD) with limited effective strategies available. We previously have shown that chikusetsusaponin IVa (CHS), a dietary saponin from herbs in South American known for their metabolic benefits, mitigates diet-induced diabetes. In this study we investigated the beneficial effects of CHS on MASLD and the underlying mechanisms. MAFLD mouse model was established by the high-fat diet (HFD) for 6 weeks and then were treated with CHS (50 mg·kg-1·d-1, i.g.) for another 8 weeks. By conducting transcriptomic analysis in palmitic acid-treated HepG2 cells and primary hepatocytes as well as lipidomic analysis in liver tissues, we demonstrated that HFD activated the intestinal farnesoid X receptor (FXR) pathway, leading to the release of FGF15/19, which in turn promoted hepatic FXR-SHP binding with cAMP-responsive element-binding protein H (CREBH), thereby inhibiting CREBH-mediated fatty acid oxidation (FAO) and ketogenesis. Intriguingly, we found that CHS improved lipid metabolism in HFD mice by suppressing the enterohepatic crosstalk of FXR-SHP to enhance CREBH transactivation. Among these, lysine-specific demethylase 1 (LSD1)-mediated histone demethylation played a crucial role in lipid metabolic reprogramming. Moreover, we identified LSD1 as a critical cellular target of CHS, directly binding to Lys661 and Tyr761 of LSD1 to inhibit its histone demethylation activity. Our results suggest that targeting intestinal LSD1 with CHS could be a promising strategy for MAFLD treatment, offering new insights into the bioavailability and efficacy of natural products.
2026-07-24 | Progressive Weakness and Hypoglycemia in a Child With Selective Eating: A Nutritional Mimic of a Fatty Acid Oxidation Disorder.
Severe selective eating in children can lead to clinically important nutritional deficiencies. We report a 5-year-old boy with autism spectrum disorder who presented with progressive weakness and hypoglycemia mimicking a fatty acid oxidation disorder (FAOD). His diet had consisted almost exclusively of white rice, and he had developed clinically significant manifestations of folate and vitamin A deficiency before this presentation. After several months of progressive weakness, he developed a generalized seizure with severe hypoglycemia and blunted ketogenesis during an intercurrent infection. Laboratory testing showed low riboflavin, low free carnitine with an elevated acylcarnitine-to-free carnitine ratio, and mild C6-C10 acylcarnitine elevations. Nerve conduction studies suggested sensory-predominant axonal neuropathy. These findings resembled multiple acyl-CoA dehydrogenase deficiency, a FAOD. Riboflavin and levocarnitine supplementation was followed by recovery of independent walking, with no recurrence over 7 years. This case illustrates a nutritional mimic of FAODs and highlights the need for nutritional and metabolic evaluation in selectively eating children with progressive weakness or hypoglycemia.
2026-02-16 | The Keto–Inflammatory Network: From Systems Biology to Biological Code
The transition from energy sufficiency to deficiency triggers complex metabolic and immune adaptations that have traditionally been viewed through a reductionist pathological lens. During early lactation, coordinated mobilization of adipose tissue, muscle protein, and bone minerals supports milk synthesis, with ketogenesis specifically arising from hepatic oxidation of non–esterified fatty acids. This review introduces the Keto–Inflammatory Network (KIN), a novel framework positioning ketonemia as an evolutionarily conserved adaptive response rather than inherent metabolic dysfunction. The KIN integrates β–hydroxybutyrate (BHB) signaling with immune modulation, epigenetic regulation, circadian rhythms, and microbiota interactions. Through mechanisms including NLRP3 inflammasome inhibition, HDAC–mediated epigenetic modifications, and HCAR2 receptor activation, ketone bodies orchestrate anti–inflammatory responses while maintaining metabolic flexibility. Building upon important precedent work recognizing beneficial roles of ketones in ruminant metabolism, this review synthesizes recent advances in immunometabolism and systems biology into an integrated framework. The KIN encompasses calcium–ketone integration through the Calci–Keto–Inflammatory Code (CKIC), temporal regulation via the Ketoinflammatory Clock, and trans–kingdom signaling through microbiota interactions. In dairy cattle, this perspective reframes periparturient ketonemia as existing on a continuum from adaptive to pathological, with biological meaning determined by integrated metabolic–inflammatory patterns rather than absolute ketone concentrations. The CKIC paradigm, while requiring prospective validation, suggests novel therapeutic approaches leveraging ketone signaling for inflammatory diseases, autoimmune conditions, and metabolic disorders while challenging traditional threshold–based ketosis management strategies. This systems–level understanding opens new avenues for precision interventions that work with, rather than against, evolved adaptive mechanisms refined through millions of years of mammalian evolution. By distinguishing ketonemia (measurable ketone elevation) from pathological ketosis (dysregulated ketone accumulation), and by integrating evidence from both ruminant and monogastric models, this review provides a comprehensive framework for next–generation metabolic medicine.
2026-02-09 | Distinct effects of ketogenic and non-ketogenic weight-loss diets on hepatic steatosis and mitochondrial metabolism in MASLD.
Weight loss is the cornerstone of therapy for metabolic dysfunction-associated steatotic liver disease (MASLD). However, the optimal dietary approach for reducing intrahepatic triglycerides (IHTG) and the mechanisms underlying steatosis resolution remain poorly defined. We investigated whether weight loss via a ketogenic diet (KD) compared with a non-ketogenic diet (ND) differentially affects IHTG content, hepatic mitochondrial metabolism, and the circulating metabolome. Individuals with varying IHTG content underwent short-term hypocaloric KD and ND in a crossover design. Before and after each diet, IHTG was quantified by proton magnetic resonance spectroscopy and liver stiffness by magnetic resonance elastography. We used state-of-the-art isotope tracer methodology to compare in vivo rates of hepatic mitochondrial tricarboxylic acid (TCA) cycle oxidation, endogenous glucose production, and β-hydroxybutyrate production (ketogenesis). Targeted plasma metabolomics by NMR and LC-MS was used to evaluate systemic metabolic responses. Despite similar energy deficits and body fat loss, IHTG decreased 45% more with KD than ND (-29% vs. -20%), accompanied by a threefold greater improvement in hepatic insulin sensitivity (59% vs. 21%). KD, but not ND, markedly reduced serum insulin concentrations (-54%), thereby promoting lipolysis and intrahepatic fatty acid partitioning toward mitochondrial β-oxidation, increasing hepatic mitochondrial [NADH]/[NAD+] (redox state) (+51%), and decreasing rates of hepatic mitochondrial TCA cycle oxidation (-34%). KD, but not ND, increased plasma concentrations of branched-chain amino acids, acylcarnitines, and TCA cycle intermediates. Both diets ameliorated MASLD, but KD produced a greater reduction in IHTG owing to a starvation-like metabolic state. However, the benefits of KD were accompanied by increased hepatic mitochondrial redox state and suppression of TCA cycle oxidation, which are features previously linked to progressive liver injury. This study provides mechanistic justification for considering dietary composition, in addition to caloric restriction, as a key determinant of steatosis resolution in metabolic dysfunction-associated steatotic liver disease (MASLD). The findings highlight a potential trade-off between greater short-term reductions in liver fat and the emergence of metabolic features previously associated with increased susceptibility to liver injury. While a ketogenic diet may facilitate rapid liver fat reduction in selected clinical contexts, its use should be approached cautiously, particularly in individuals with advanced MASLD. These results underscore the need for systematic evaluation of dietary composition as a determinant of both efficacy and safety of nutritional interventions for MASLD. NCT03737071.
2025-07-01 | The Multifaceted Influence of Beta-Hydroxybutyrate on Autophagy, Mitochondrial Metabolism, and Epigenetic Regulation.
Beta-hydroxybutyrate (BHB), a key ketone body produced during fatty acid metabolism, plays critical roles in various physiological and pathological conditions. Synthesized in the liver through ketogenesis, BHB serves as an essential energy substrate during glucose deprivation, supporting survival by efficiently utilizing fat reserves. It crosses the blood-brain barrier, providing energy for neuronal function, enhancing cognitive processes such as learning and memory, and offering neuroprotection by modulating synaptic plasticity and neurotransmitter levels. BHB's impact extends to cellular pathways, including autophagy, mitochondrial biogenesis, and epigenetic regulation. By modulating autophagy, BHB ensures mitochondrial integrity and function through intricate molecular pathways involving AMPK, mTOR, PINK1/Parkin, and others. This regulation plays vital roles in neurodegenerative diseases, metabolic disorders, cancer, and cardiovascular diseases, reducing oxidative stress and preventing cellular dysfunction. Epigenetically, BHB acts as an endogenous histone deacetylase inhibitor, inducing beneficial histone modifications that enhance cellular resilience and stress responses. This epigenetic influence is crucial in conditions like diabetes and cancer, aiding insulin secretion, protecting pancreatic beta cells, and impacting cancer cell gene expression and survival. Furthermore, BHB's therapeutic potential is evident in its ability to improve mitochondrial function across various tissues, including neurons, muscle, and liver. By enhancing mitochondrial respiration, reducing oxidative stress, and altering metabolic pathways, BHB mitigates conditions such as ICU-acquired weakness, nonalcoholic fatty liver disease, and cardiovascular diseases. BHB's modulation of autophagy and epigenetic regulation underscores its comprehensive role in cellular homeostasis and health across multiple physiological contexts, providing a foundation for future therapeutic strategies.
2024-11-21 | Identification of chikusetsusaponin IVa as a novel lysine-specific demethylase 1 inhibitor that ameliorates high fat diet-induced MASLD in mice.
Diet-induced metabolic dysfunction steatotic liver disease (MASLD) is also called as non-alcoholic fatty liver disease (NAFLD) with limited effective strategies available. We previously have shown that chikusetsusaponin IVa (CHS), a dietary saponin from herbs in South American known for their metabolic benefits, mitigates diet-induced diabetes. In this study we investigated the beneficial effects of CHS on MASLD and the underlying mechanisms. MAFLD mouse model was established by the high-fat diet (HFD) for 6 weeks and then were treated with CHS (50 mg·kg-1·d-1, i.g.) for another 8 weeks. By conducting transcriptomic analysis in palmitic acid-treated HepG2 cells and primary hepatocytes as well as lipidomic analysis in liver tissues, we demonstrated that HFD activated the intestinal farnesoid X receptor (FXR) pathway, leading to the release of FGF15/19, which in turn promoted hepatic FXR-SHP binding with cAMP-responsive element-binding protein H (CREBH), thereby inhibiting CREBH-mediated fatty acid oxidation (FAO) and ketogenesis. Intriguingly, we found that CHS improved lipid metabolism in HFD mice by suppressing the enterohepatic crosstalk of FXR-SHP to enhance CREBH transactivation. Among these, lysine-specific demethylase 1 (LSD1)-mediated histone demethylation played a crucial role in lipid metabolic reprogramming. Moreover, we identified LSD1 as a critical cellular target of CHS, directly binding to Lys661 and Tyr761 of LSD1 to inhibit its histone demethylation activity. Our results suggest that targeting intestinal LSD1 with CHS could be a promising strategy for MAFLD treatment, offering new insights into the bioavailability and efficacy of natural products.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
2 orphan drug designations for Disorder of fatty acid oxidation and ketogenesis, including 1 approved therapy.
2 orphan drug designations for Disorder of fatty acid oxidation and ketogenesis, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Sodium (4-{(E)-3-(4-fluorophenyl)-3-[4-(3-morpholin-4-yl-prop-1ynyl)phenyl]allyloxy}-2-methylphenoxy)acetate | small molecules | FDA | 2019-07-22 | — | Reneo Pharma Ltd |
triheptanoin [Dojolvi] | small molecules | FDA | 2015-04-15 | 2020-06-30 | Ultragenyx Pharmaceutical, Inc. |
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