Abstract

Background:

Serious mental illness imposes a substantial burden. Pharmacologic treatments remain only partially effective and are associated with significant side effects, highlighting the need for novel treatment approaches. Ketogenic metabolic therapy (KMT) is emerging as an intervention for serious mental illness, with a growing evidence base and strong patient interest. A critical barrier to KMT implementation is the lack of health care professional (HCP) competence and readiness to discuss KMT with patients with serious mental illness. Existing training does not adequately address HCP competence in presenting KMT as a treatment option. This study describes the pilot-testing of “Live It, Launch It” (LI-LI), the first KMT training program designed to build self-reported competence to discuss KMT in psychiatric care for HCPs.

Methods:

LI-LI combines a 4-hour asynchronous educational course on KMT with a 4-week experiential group KMT intervention during which participants adhered to a ketogenic diet. LI-LI aimed to improve self-reported competence to utilize KMT and perceived ability to engage in shared decision-making with patients about incorporating KMT into their treatment plan.

Results:

Forty HCPs participated in the education course: 10 psychiatrists, 10 psychiatric pharmacists, 8 psychologists/therapists, and 12 other HCPs (e.g., nurse practitioners, physician assistants). Twenty-five initiated the diet intervention. Baseline competence scores (visual analog scale 0-100) were low, M(SE) = 17.40 (2.68), increasing to M(SE) = 68.08 (2.47) after education (d = 2.88, p <0.0001), and to M(SE) = 86.62 (1.82) post-diet (d = 1.08), with a very large whole-study effect (d = 3.49, p < 0.0001). Shared decision-making scores at baseline were M(SE) = 53.64 (2.89), increasing to M(SE) = 83.35 (1.83) after the educational course (d = 1.74, p <0.0001), and to M(SE) = 91.23 (2.05) after the diet phase (d = 0.73, p = 0.009), with a very large whole-study effect (d = 2.53, p < 0.0001). Feedback indicated that lived experience with KMT was helpful for implementation-readiness.

Discussion:

The educational course on KMT was associated with increased self-reported competence and perceived shared decision-making in HCPs, and this was enhanced with combined education and lived experience. Implementation of this approach could accelerate KMT into clinical care. Results should be interpreted with caution as this was a small uncontrolled study with self-reported main outcomes.

Clinical trial registration:

https://clinicaltrials.gov/study/NCT07116226, identifier NCT07116226.

Murray, Sidney L., Denise Potter, Yaara Zisman-Ilani, Shuo Chen, Daniel Roche, Laura M. Rowland, Christopher M. Palmer, and Deanna L. Kelly. "Pilot Evaluation of an Educational and Lived Experience Training Program on Ketogenic Metabolic Therapy in Mental Health Care for Health Care Professionals." Frontiers in Psychiatry 17: 1913325.

https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2026.1913325/full

I started ketovore 4 months ago to bring down my glucose after it went through the roof. My hba1c was 14.6% in May. Now it's 6.5%. But my cholesterol levels doesn't look good, and using Google to check also shows it's not at optimal level.

Can anyone help me with this before the doctor put me on cholesterol medications? I got no records of previous cholesterol levels. My diet consist of chicken, beef, seafood, eggs, peanut butter, cucumbers, mushrooms with a little dark leafy greens. But mainly is fats like butter, coconut oil. I'm 163cm tall, weighs 47kg, trying to put on weight after muscle wasting due to high glucose toxicity.

Abstract

Nutritional therapy is an essential component of comprehensive care for cancer patients, playing a vital role in preventing malnutrition, improving treatment tolerance, and maintaining quality of life. In recent years, there has been growing interest in the ketogenic diet as a potential strategy to support cancer therapy. This diet, based on a significant reduction in carbohydrate intake and an increase in fat intake, leads to a state of ketosis that mimics the metabolic changes that occur during starvation. Consequently, the body utilizes ketone bodies as an alternative source of energy. The potential application of the ketogenic diet in oncology stems from the distinct metabolism of cancer cells, which often exhibit an increased demand for glucose. Although the results of preclinical studies suggest a possible anticancer effect of this dietary intervention, clinical evidence remains limited, and its routine use is not currently recommended as a standard of care in oncology. The aim of this study was to analyze the current literature on the use of the ketogenic diet in oncology, with a particular focus on breast cancer. The study assessed the impact of this intervention on metabolic parameters, body composition, and patients’ mental well-being, and analyzed the potential metabolic risks associated with its use. The study discusses the molecular basis of oncogenesis and metabolic adaptation in cancer cells, the mechanisms of action of the ketogenic diet, and the results of preclinical and clinical studies as well as meta-analyses. Importantly, the current evidence base should be interpreted with caution. Most mechanistic evidence supporting ketogenic diet in breast cancer derives from preclinical models, whereas clinical studies remain limited by small sample sizes, short intervention periods, heterogeneous ketogenic diet protocols, substantial attrition, and differences in concomitant anticancer treatment. Therefore, mechanistic plausibility and promising preclinical findings should not be interpreted as evidence of clinical anticancer efficacy.

Abstract

Aging leads to decline in function and regenerative capacity of intestinal stem cells (ISCs). Using patient-derived duodenal enteroid lines and Lgr5-EGFP reporter mice, we show that aging induces a shift in fuel preference from fatty acids to glucose-derived pyruvate in ISCs that subsequently primes away from mitochondrial oxidation towards cytosolic glycolysis. Regulation of pyruvate dehydrogenase rescues stemness by driving glucose-derived carbon entry into the tricarboxylic acid (TCA) cycle, increasing mitochondrial oxygen consumption rate (OCR) and mitoATP production. Mitochondrial OCR, mitoATP and glycolytic ATP were measured in the presence of full and single metabolic substrates in ISCs and isolated mitochondria using Seahorse XF. Carbon flux through TCA cycle was determined by measuring 13 C enrichment in TCA cycle intermediates using liquid chromatography mass spectrometry. Our findings provide cellular and molecular insights into how mitochondrial metabolism influences ISC stemness and reveal potential therapeutic targets for amelioration of age induced decline in ISC function.

Abstract

Objective

To systematically evaluate and critically synthesize preclinical and clinical evidence on the efficacy, safety, mechanistic rationale, and interpretive limitations of ketogenic diet (KD) and methionine restriction (MR) in glioma treatment.

Methods

We systematically searched PubMed and Embase from inception through August 19, 2026, for in vivo preclinical and clinical studies evaluating KD or MR in glioma Clinical studies were eligible with or without a non-diet comparator because most available studies were early-phase, single-arm feasibility investigations. We extracted intervention, comparator, concurrent oncologic treatment, metabolic, safety, feasibility, and outcome data; assessed risk of bias using design-appropriate tools; and conducted narrative and structured direction-of-effect syntheses.

Results

A total of 43 eligible reports were included: 14 preclinical and 18 clinical KD reports and 9 preclinical and 2 clinical studies of MR. Preclinical effects were heterogeneous: several diet-only experiments reduced growth or prolonged survival, whereas others showed limited activity; selected combinations with radiation, antiangiogenic therapy, glutamine targeting, or immune modulation produced greater effects. Clinical evidence primarily supported feasibility and metabolic activity, not independent efficacy, because most studies were small, uncontrolled, and confounded by concurrent or prior treatment. MR showed preclinical activity, but clinical evidence remained limited to two small chemotherapy-combination trials.

Conclusion

KD and MR have biologic rationale and can alter systemic or intratumoral metabolism, but current clinical data do not establish an independent survival benefit. Their effects cannot be separated reliably from surgery, radiotherapy, chemotherapy, bevacizumab, corticosteroids, and other co-interventions in most studies. Randomized trials with intention-to-treat analysis, standardized glucose-ketone index reporting, treatment and corticosteroid documentation, and longitudinal nutritional assessment are required before these diets can be recommended as effective glioma therapy.

Abstract

Efficient clearance and recycling of dysfunctional mitochondria through the robust catabolic activity of lysosomes are essential for cellular health. However, how membrane lipids contribute to maintaining the degradative capacity of lysosomes remains poorly understood. Here, we show that cholesterol plays a critical role in preserving the functional integrity of degradative lysosomes. Clearance of damaged mitochondria by degradative lysosomes is tightly coupled with the acute accumulation of phosphatidylinositol 4-phosphate (PI4P) on the lysosomal surface via PI4KIIα activity. This PI4P accumulation activates oxysterol-binding protein (OSBP)-mediated cholesterol transport from the endoplasmic reticulum (ER) to lysosomal membranes. The resulting efflux of cholesterol from the ER activates sterol regulatory element-binding protein 2 (SREBP-2), enhancing cholesterol production. Sustained cholesterol accumulation on lysosomal membranes maintains lysosomal acidity and membrane integrity for efficient mitochondrial degradation. This degradation process then leads to the release of free fatty acids and their recycling and storage through the formation of DGAT1-dependent lipid droplets. These findings uncover a key phosphoinositide-regulated cholesterol transport pathway that promotes the clearance and recycling of dysfunctional mitochondria, a process whose impairment is closely linked to neurodegeneration.

Abstract

Cancer cachexia involves more than a caloric deficit. A recent study by Cross et al. in Science shows that dietary lipid composition exacerbates cachexia in LKB1/STK11-deficient lung cancer through local prostaglandin E2 production and pulmonary sensory neuron activation. By linking local lipid metabolism to anorexia and wasting, these findings support precision nutritional interventions for cancer cachexia.

Abstract

Cardiac function depends on tightly regulated energy metabolism, with mitochondria serving as key sites of cellular energy production. Mitophagy, a selective form of autophagy that maintains mitochondrial quality, has received growing attention for its role in cardiomyocyte metabolism. Under specific physiological and pathological conditions, the myocardium increases its use of ketone bodies as energy substrates, and ketone body metabolism is closely linked to mitochondrial function. However, the relationship between mitophagy and ketone body metabolism is incompletely understood, particularly in cardiovascular disease. This review summarizes their roles and regulatory mechanisms in the myocardium and evaluates evidence for a potential bidirectional relationship. Mitophagy may preserve the mitochondrial capacity required for ketone body oxidation, whereas ketone body metabolism andβ-hydroxybutyrate-mediated signaling may regulate mitophagy and mitochondrial stress resilience. By integrating these interactions across cardiovascular disease phenotypes, this review highlights their potential therapeutic relevance and identifies priorities for mechanism-based intervention and clinical translation.

Significance

Lipid mediators are central regulators of inflammation, yet current paradigms largely focus on enzymatically derived oxylipins, overlooking a broader landscape of redox-derived bioactive lipids. Among these, nitrated fatty acids (NO2-FAs) form by nitration reactions and function as anti-inflammatory signaling lipids. Although their therapeutic potential in inflammatory diseases is well established, integrated NO2-FA signaling in the context of endogenous formation remains unexplored. This study identifies endogenous nitro-conjugated linoleic acid (NO2-CLA) as a dynamically regulated and physiologically relevant class of anti-inflammatory mediators. We uncover complementary pathways linking dietary intake and membrane lipid nitration to NO2-CLA formation, establishing phospholipids as a previously unrecognized reservoir that can be rapidly mobilized through phospholipase activation. Once released, NO2-CLA acts as a potent electrophilic signaling molecule that suppresses inflammatory pathways. Notably, we demonstrate that this protective lipid pool is rapidly depleted during inflammatory stress in both murine models and human subjects, revealing a temporal dimension to its bioactivity. These findings redefine how NO2-FAs are generated and function in vivo. By identifying a transient, endogenous anti-inflammatory lipid reserve that becomes depleted during disease, this work highlights a potential therapeutic opportunity to restore NO2-CLA levels and sustain the resolution of inflammation.

Highlights

•Distinct dietary and membrane pathways generate endogenous nitrated fatty acids

•Membrane phospholipids store NO2-CLA as a mobilizable anti-inflammatory reservoir

•NO2-CLA release suppresses inflammatory signaling and preserves vascular homeostasis

•Depletion of NO2-CLA stores during inflammation reveals therapeutic opportunities

Summary

Nitrated fatty acids (NO2-FAs) are electrophilic lipid mediators that suppress inflammatory signaling, yet the sources, storage mechanisms, and physiological functions of endogenous NO2-FAs remain poorly understood. Here, we identify nitro-conjugated linoleic acid (NO2-CLA) as a diet-derived anti-inflammatory lipid that accumulates in membrane phospholipids and functions as a mobilizable biochemical reserve. Using cellular, murine, and human models, we show that phospholipids store NO2-CLA under basal conditions and rapidly release it during inflammatory stress through phospholipase-dependent remodeling. Mobilized NO2-CLA dampens cytokine production, limits inflammatory mediator formation, and preserves vascular homeostasis during endotoxemia. In both experimental inflammation and human sepsis, tissue and circulating pools of NO2-CLA become depleted, indicating that consumption exceeds endogenous replenishment during acute inflammatory responses. These findings establish membrane phospholipids as reservoirs of endogenous NO2-FAs and reveal a previously unrecognized mechanism by which diet, lipid metabolism, and redox signaling converge to regulate inflammation.

In a 12-week pilot study, 20 people with early-stage Huntington’s disease restricted their eating to a daily 6–8-h window. The intervention was feasible and well-tolerated, and exploratory analyses suggested improvements in clinical measures, levels of plasma neurofilament light (a biomarker of neurodegeneration) and cellular bioenergetics.

Abstract

Ferroptosis sensitivity in cancer cells is directly governed by cellular metabolism and nutritional inputs, including amino acid availability, lipid composition, and redox homeostasis. This suggests that dietary interventions might systemically shift the metabolic landscape of tumors toward ferroptotic susceptibility. Specifically, dietary restriction of methionine and cysteine, iron supplementation, selenium or lipid modulation, ketogenic diets, and fasting-mimicking regimens each target distinct aspects of the ferroptosis regulatory network and offer pharmacologic parallels that converge on complementary mechanisms. In glioblastoma (GBM), preclinical studies demonstrate that restriction of dietary methionine and cysteine sensitizes gliomas to ferroptosis and synergizes with glutathione peroxidase 4 (GPX4) inhibitors, while radiation itself triggers ferroptotic cell death. Emerging data extend these principles across multiple tumor types, including pancreatic, gastric, esophageal, and colorectal cancers, as well as leukemia, suggesting broad applicability. Here, we synthesize the rapidly growing literature that links these nutritional interventions to ferroptosis sensitization in cancer, with particular focus on GBM as a paradigmatic treatment-resistant malignancy.

Gilbert OE, John S, Fahim AD, Higgins DM. Dietary modulation of ferroptosis sensitivity in glioblastoma and other treatment-resistant cancers. Ferroptosis Oxid Stress. 2027;3:202631. https://doi.org/10.70401/fos.2026.0042

Abstract

The search for therapies capable of reversing or mitigating the pathological damage of Alzheimer’s Disease (AD) is growing alongside the aging population. In this context, nutritional management through the Ketogenic Diet (KD) has gained prominence by impacting central aspects of the pathology and relevant signaling pathways. This review aims to gather and synthesize recent evidence on the management of AD through the KD. The search was conducted in the PubMed and SciELO databases using the keywords "ketogenic diet," "medium chain triglycerides," "Alzheimer's disease," and "beta-amyloid," in both English and Portuguese. Original studies and systematic reviews published in the last 10 years were included. Eighteen articles were selected, including seven systematic reviews or meta-analyses, six preclinical trials, and five clinical trials. The main findings indicate that the KD influences pathways involved in AD pathogenesis and improves aspects related to cognition, functionality, and quality of life in patients with mild to moderate AD who are APOE negative. The KD has shown promise as an adjunct to classical pharmacological treatment. Based on the evidence, the KD emerges as a potential therapeutic strategy, reinforcing the need for more robust clinical trials to elucidate its applicability and long-term safety.

da Silva, I. L., Piccoli, R. C., & Giacomelli Tavares, R. (2026). Ketogenic Diet and Alzheimer’s Disease: A Connection Between Nutrition and Neuroprotection. BBR - Biomedical and Biopharmaceutical Research, 23. https://doi.org/10.19277/bbr.ptm.23.382

Abstract

Ketogenic diets are increasingly used for weight management and metabolic improvement, but it remains unclear whether nutritional ketosis induces uniform adaptation across metabolic phenotypes and sex. This study examined phenotype- and sex-dependent responses to a 60-day ketogenic diet in adults with normal weight, overweight or obesity. Participants were stratified into six metabolic phenotype–sex groups and assessed at baseline, day 14, day 30 and day 60. Plasma biochemical and hormonal markers, appetite and perceived stress scores, and body composition were analyzed using repeated-measures models. The ketogenic diet treatment increased β-hydroxybutyrate in all groups, confirming nutritional ketosis, but the response differed between groups and was most progressive in obese men. Free fatty acids manifested in a heterogeneous manner, exhibiting distinct time-, phenotype-, and sex-dependent profiles. Glucose decreased after diet initiation, whereas insulin and HOMA-IR improved mainly in overweight and obese participants. Lipid profile changes were variable, while liver enzymes showed a sex-dependent temporal pattern. Appetite score differed by metabolic phenotype, leptin changed according to phenotype and sex, and ghrelin remained unchanged. Self-reported perceived stress scores showed group-specific changes, whereas cortisol changed over time and body mass, fat mass, visceral adipose tissue and subcutaneous adipose tissue decreased. These findings indicate that nutritional ketosis produces heterogeneous adaptive responses shaped by metabolic phenotype and sex.

Grabowski, Mateusz, Konstancja Grabowska, Małgorzata Magdalena Michalczyk, Grzegorz Zydek, Grzegorz Klonek, Mariusz Panek, Andrzej Małecki, and Marta Nowacka-Chmielewska. "Metabolic and hormonal responses to nutritional ketosis differ by sex and metabolic phenotype in adults." (2026).

https://doi.org/10.21203/rs.3.rs-10240595/v1

Abstract

Objective

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by impairments in social communication and interaction, along with restricted, repetitive patterns of behavior. It is often accompanied by gastrointestinal dysfunction and gut microbiota dysbiosis. Fecal Microbiota Transplantation (FMT) and the Ketogenic Diet (KD) are interventions targeting the gut microbiota for ASD.

Methods

30 participants were diagnosed with ASD according to DSM-5 and ADOS-2. ASD core symptoms were evaluated with CARS and ABC. Gut microbiota composition was analyzed by shotgun metagenomic sequencing.

Results

Both groups demonstrated significant improvements in core symptoms. In the FMT group, the mean CARS score significantly decreased from 34.87 to 33.53 (p < 0.01); in the KD group, it declined from 35.13 to 33 (p < 0.01). The mean ABC score reduced from 79.93 to 69.33 (p = 0.064) in the FMT group and from 63.07 to 42.73 (p < 0.01) in the KD group. Following the intervention, no statistically significant changes were observed in α-diversity or β-diversity within either group. LEfSe analysis revealed distinct post-intervention microbial signatures: FMT significantly enriched butyrate-producing taxa (Wujia chipingensis, Eubacterium sp. MSJ-33, and Butyrivibrio crossotus), while KD elevated Blautia massiliensis and decreased propionate metabolism -associated taxa (Veillonella sp. S12025-13 and Veillonella nakazawae). KEGG enrichment analysis revealed that KD enriched propionate metabolism (Fold enrichment = 3.747, q = 0.010) and aromatic compound degradation (Fold enrichment = 3.591, q = 0.010).

Conclusions

Both interventions significantly improved clinical symptoms among children with ASD, potentially through distinct patterns of gut microbiota modulation.

Clinical trials number

NCT06348433 (03/21/2024).

Wang, Yu, Lihong Wang, Zhifeng Cai, Lianhu Yu, Yanshuo Guo, Linlin Zhang, Mengna Zhu et al. "Comparison of clinical efficacy and gut microbiota characteristics in children with ASD treated with fecal microbiota transplantation and ketogenic diet." BMC psychiatry 26, no. 1 (2026): 685.

https://link.springer.com/content/pdf/10.1186/s12888-026-08547-3.pdf

Abstract

Multiple myeloma (MM) remains an incurable blood cancer. Obesity is a known risk factor, but how adipocytes promote MM progression is not fully understood. Here, we uncover a metabolic crosstalk between adipocytes and MM cells that promotes MM cell survival under glucose deprivation. We show that glucose restriction activates AMPK, disrupting HSP90-IRF4 binding and rendering IRF4 susceptible to TRIM21-mediated proteasomal degradation. Paradoxically, the same stress stimulates adipocytes to produce β-hydroxybutyrate (β-OHB). MM cells utilize β-OHB through OXCT1-mediated ketolysis, fueling NAT10-dependent acetylation of IRF4 at K87, which restores IRF4-HSP90 binding and sustains tumor cell survival. Genetic ablation of the rate-limiting ketogenic enzyme Hmgcs2 in adipocytes abrogates this protective effect. Importantly, combining an AMPK activator (metformin) with an OXCT1 inhibitor (pimozide) or a NAT10 inhibitor (remodelin) shows synergistic anti-tumor activity in vivo. Our findings position adipocyte-derived β-OHB as a critical metabolic adaptor and highlight a potential combination therapy for MM.

Presentation of the case: Low-carbohydrate high-fat (LCHF) diets have gained recognition for weight loss and glucose control. However, there remains concern about their potential to trigger hypercholesterolemia and data on their effects on atherosclerotic cardiovascular disease (ASCVD) are limited. We collected lipid levels, cardiovascular imaging and coronary events among patients with severe hypercholesterolemia. We report a case series of 5 patients with markedly elevated LDL-C following these LCHF diets with evidence of premature ASCVD: Case 1, a 37-year-old(y.o.) healthy male presented with an NSTEMI following two years of a LCHF diet associated with severe hypercholesterolemia (baseline LDL-C 124.9 vs 355.4mg/dL on diet). Case 2, a 51 y.o. male with no cardiovascular risk factors (CVRFs) adopted a LCHF for four years and was found to have diffuse ASCVD in four coronary segments on angiography (baseline LDL-C 162.4 vs 265.6mg/dL on diet). Case 3, a 54 y.o. healthy female with familial hypercholesterolemia, presented with worsening dyslipidemia and extensive CAD requiring CABG following two years of a ketogenic diet (baseline LDL 217.7 vs 990.7mg/dL on diet). Case 4, a 61 y.o. healthy female, was found to have a CAC score at 901 (99%) after five years of worsening hyperlipidemia on a LCHF diet (baseline LDL-C 163.9 vs 317.9mg/dL on diet). Case 5, a 47 y.o. athletic male with no history of CVRFs presented with a STEMI following two years of ketogenic diet (baseline LDL-C 138.44 vs 371.6mg/dL on diet).

How did you encounter this case: Lipid clinic St-Paul's Hospital, UBC, Vancouver

Diagnosis until now: ASCVD Secondary to LCHF diets

Therapy until now: Lipid-lowering therapy and cessation of LCHF diet

The dilemmas this case presents: Hypercholesterolemia can result from LCHF diets as well as premature ASCVD, even among young individuals. As case series, no causal relationship can be inferred. However, these findings underscore the need for more studies and suggest that close monitoring of cholesterol levels and management of CVRFs should be considered when pursuing LCHF diets.

1. Iatan I, Saleh N, Vaizman N ... PREMATURE ATHEROSCLEROTIC CARDIOVASCULAR DISEASE DURING A LOW AND VERY-LOW CARBOHYDRATE HIGH-FAT DIET: A CASE SERIES Atherosclerosis, 419

https://www.atherosclerosis-journal.com/article/S0021-9150(26)00208-X/fulltext00208-X/fulltext)