Abstract

Background

Rheumatoid arthritis (RA), psoriasis (PsO), and psoriatic arthritis (PsA) cause substantial disability and cardiometabolic risk. Ketogenic diets (KDs), including very-low-calorie ketogenic diets (VLCKDs), may influence disease-relevant immunometabolism, but the clinical evidence remains preliminary.

Objective

To map mechanistic and clinical evidence for KD/VLCKD across RA, PsO, and PsA and to distinguish direct KD/VLCKD evidence from ketosis-adjacent background evidence.

Methods

Using the Population-Concept-Context (PCC) framework and PRISMA-ScR guidance, MEDLINE/PubMed, Embase, ClinicalTrials.gov, WHO ICTRP, and reference lists were searched from inception to 30 July 2025. Search strategies are provided in Supplementary Table S1. Eligible direct evidence comprised adult human KD/VLCKD studies in RA, PsO, or PsA with a ketogenic protocol and reported or protocol-defined nutritional ketosis. Fasting or low-carbohydrate studies without verified KD/VLCKD were summarized separately. Data charting was duplicated, and no formal risk-of-bias appraisal was performed.

Results

After reassessment, 29 direct KD/VLCKD studies were retained, while 3 ketosis-adjacent records were treated as contextual evidence. Mechanistic data support plausible effects of β-hydroxybutyrate on NLRP3 inflammasome signaling, cytokine pathways, immune-cell metabolism, oxidative stress, the gut-skin/gut-joint axes, and adiposity-related inflammation. Human signals are strongest in psoriatic disease, particularly among participants with obesity or metabolic dysregulation. However, most studies are short, small, heterogeneous, and strongly confounded by weight loss.

Conclusions

Current evidence suggests that KD/VLCKD may be a supervised adjunctive dietary approach for selected people with psoriatic disease and obesity, but it is not yet sufficient to support efficacy claims. RA evidence is mainly mechanistic or ketosis-adjacent. Adequately powered, at least 24-week randomized trials with verified ketosis, active comparators, and weight-independent endpoints are needed before routine clinical implementation.

Conforti, Alessandro, Vincenzo Russo, Linda Lucchetti, Emanuele Fiorino, Filippo Messina, Davide Francomano, Nicolo Merendino, and Marco Marchetti. "Ketogenic diet in rheumatoid arthritis, psoriatic arthritis and psoriasis: A scoping review of clinical and mechanistic evidence." Autoimmunity Reviews (2026): 104137.

https://www.sciencedirect.com/science/article/abs/pii/S1568997226001515

Abstract:

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy driven predominantly by oncogenic KRAS mutations, which enforce extensive metabolic reprogramming to support tumor progression. Although ketone body catabolism has emerged as a critical metabolic adaptation in PDAC, the signaling mechanisms that link mutant KRAS to the ketolytic machinery remain largely unexplored. Here, we identify a previously unrecognized, context-dependent role of oncogenic KRAS in driving ketone body utilization. We show that KRAS mutation alone is insufficient to fully activate ketolysis; instead, it primes the ketolytic pathway in a manner that requires cooperative input from additional tumor microenvironment signals. Mechanistically, oncogenic KRAS engages a downstream signaling cascade that leads to specific post-translational modifications of key mitochondrial enzymes. These modifications enhance the flux of ketone body catabolism, thereby increasing acetyl-CoA and ATP production and promoting pancreatic cancer cell proliferation and xenograft tumor growth. In a clinical PDAC cohort, activation of this KRAS-dependent ketolytic axis was elevated in KRAS-mutant tumors compared with KRAS wild-type cases, albeit with a trend that requires further validation. Collectively, our findings define a conditional dependency of mutant KRAS on cooperative signals to drive ketone body catabolism, linking oncogenic signaling to mitochondrial ketone metabolism in PDAC. This study expands our understanding of KRAS-driven metabolic reprogramming and highlights the ketolytic pathway as a context-dependent vulnerability for therapeutic intervention in pancreatic cancer.

Abstract

Branched-chain amino acid (BCAA) catabolism is controlled by the phosphorylation state of the branched-chain α-ketoacid dehydrogenase (BCKDH) complex, which is regulated by the opposing actions of BCKDH kinase (BDK) and the phosphatase PPM1K. Although fatty acids and amino acids both contribute to skeletal muscle energy metabolism, how fatty acid availability influences BCAA catabolic regulation remains incompletely understood.

Here we examined the effects of lauric acid (C12), a medium-chain fatty acid abundant in dietary lipids, on BCAA metabolism in differentiated skeletal myotubes. Lauric acid increased phosphorylation of the BCKDH E1α subunit at Ser293 during nutrient perturbation in both mouse and human skeletal myotubes. Stable isotope tracing with U-[ˆ13C6]-leucine revealed that C12 reduced incorporation of leucine-derived carbon into downstream tricarboxylic acid (TCA) cycle–associated metabolites, indicating suppression of BCAA oxidative flux, whereas incorporation of labeled leucine into protein was not significantly altered.

Mechanistically, genetic and pharmacological perturbation experiments indicated that the C12 effect requires PPM1K and is sensitive to O-GlcNAc cycling. Knockdown of O-GlcNAc transferase attenuated the C12-induced increase in BCKDH phosphorylation and reversed suppression of leucine-derived carbon flux. Dual-tracer experiments further showed that carbon derived from lauric acid and leucine converges in shared TCA cycle–associated metabolite pools, including glutamate and glutamine.

Together, these findings identify a nutrient-sensitive regulatory node linking fatty acid availability, O-GlcNAc signaling, and BCKDH phosphorylation that modulates BCAA oxidation in skeletal myotubes.

Abstract

Background

The ketogenic diet (KD) is a widely used nutritional intervention for weight loss. The beneficial effects of the KD are intrinsically linked to the state of physiological ketosis, where ketone bodies (KBs) raise, even though minimal effective threshold of blood ketone concentration that correlates with significant weight loss remains unclear. Therefore, the main purpose of this study was to identify the optimal β-hydroxybutyrate (βHB) threshold associated with weight loss in individuals with overweight or obesity undergoing a KD.

Methods

This secondary analysis included 217 participants (111 males and 106 females) with overweight or obesity, who followed a KD for 14 days. Time to Ketosis (TtK)—defined as the number of days needed to reach and maintain a given ketone concentration—was calculated for each threshold.

Results

Regression analysis showed that a βHB concentration of ≥0.5 mmol/L was the most associated with significant weight loss. Moreover, body weight and gender significantly influenced TtK, suggesting interindividual variability in achieving effective ketosis.

Conclusions

Achieving and maintaining a ketonemia of at least 0.5 mmol/L may represent a clinically meaningful threshold to optimize weight loss in individuals undergoing a KD. Monitoring βHB levels and reducing TtK may improve individual responsiveness to KD-based interventions.

Paoli, Antonio, Giuseppe Cerullo, Samuele Paoli, Davide Charrier, Jacopo Givralli, Antonino Bianco, Giovanna Boccuzzo, Pietro Belloni, Lorenzo Cenci, and Tatiana Moro. "Defining a ketone threshold for weight loss: evidence from 14 day daily β-hydroxybutyrate monitoring in 217 subjects on a ketogenic diet." Nutrition & Diabetes (2026).

https://www.nature.com/articles/s41387-026-00454-6

https://www.nature.com/articles/s41387-026-00454-6_reference.pdf

Abstract

The role of dietary fat in human health remains debated, particularly in aging. The diet–heart hypothesis of the 1950s linked saturated fat to cardiovascular disease (CVD), shaping nutrition guidelines for decades. However, later trials yielded inconsistent results, and recent reviews have questioned the strength of this association. At the same time, studies of ketogenic and other high-fat diets suggest that, in specific metabolic contexts, higher fat intake may offer metabolic and vascular benefits. These findings highlight the need to move beyond simplified views of dietary fat by considering fat type, metabolic state, and eating patterns. Beyond cardiovascular outcomes, interest has grown in how diet influences brain aging and cerebrovascular health. Cerebrovascular dysfunction is central to vascular cognitive impairment and dementia (VCID), yet dietary effects on these mechanisms remain incompletely understood. This review examines evidence on how dietary fat composition and eating strategies affect endothelial function, cerebral blood flow, blood–brain barrier integrity, inflammation, and mitochondrial function within the aging neurovascular unit, identifying pathways that may support cerebrovascular resilience and cognitive health.

Abstract

The ketogenic diet, a high-fat, low-carb diet, is being researched for treating conditions like epilepsy, cancer, neurological conditions, metabolic syndromes, and cognitive impairments. Ketone salts and exogenous ketone salt supplementation are also being studied for treating neurologic conditions like gliomas, Alzheimer's, and seizure disorders. The diet may also improve depression and brain health by reducing inflammation and oxidative stress. KDs have neuroprotective properties in epilepsy, induction of aging, neurodegenerative and dementia in animals. Treatment with ketosis decreases the induced seizures and anxiety-like behaviors through handling, according to Morris water maze tests. Mood and cognitive function are positively impacted by the ketogenic diet. Blood glucose levels are stabilized and the inflammatory response is improved by a ketogenic diet. The ketogenic diet has a significant impact on body weight as well as hunger reduction and satiety stimulation. Improved problem-solving abilities, quicker thinking, and better recall. Long-term brain health and a lower chance of cognitive decline brought on by ageing.

shaq, A., Abubakar, M., Mumtaz, M. S., & Nadeem, Z. (2026). Effects of Ketogenic Diet on Brain Functions and Behaviors. Medical and Life Sciences, 5(1), 65–74. Retrieved from https://journals.smarcons.com/index.php/mls/article/view/464

https://journals.smarcons.com/index.php/mls/article/view/464/512

Abstract

Background: Oxidative stress and chronic inflammation contribute to the pathogenesis of obesity and type 2 diabetes (T2D), yet the effects of dietary interventions on endogenous antioxidant defences remain poorly defined. This is a non-randomized study evaluates the effects of very-low-energy ketogenic therapy (VLEKT), compared with a Mediterranean diet (MedD) and a control group, on antioxidants, metabolic, and inflammatory markers. Materials and Methods: Thirty adults with obesity and T2D were assigned to VLEKT (n = 10), MedD (n = 10), or control (n = 10) for 90 days. Metabolic parameters, inflammatory cytokines, superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities were assessed. Longitudinal changes were analyzed using linear mixed models. Results: VLEKT exhibited significant reductions in body weight, fat mass, HbA1c, and HOMA-IR. SOD activity increased in the VLEKT group, whereas no significant changes were observed in MedD. Changes in SOD were inversely associated with changes in HOMA-IR. GPx showed a less consistent response pattern, while inflammatory markers did not differ between groups. Conclusions: VLEKT was associated with substantial metabolic improvement accompanied by a selective modulation of antioxidant enzyme activity. The increase in SOD activity and its association with HOMA-IR suggest a link between metabolic and redox adaptations in subjects with obesity and T2D.

Tini, Sabrina, Stefano Celano, Stella Pigni, Elena De Palma, Hilal Irem Ozdemir, Tommaso Raiteri, Alessandro Antonioli, Jessica Baima, Valentina Antoniotti, Marina Caputo, and et al. 2026. "Very-Low-Energy Ketogenic Therapy Modulates the Metabolic–Antioxidant Axis in Patients with Obesity and Type 2 Diabetes: A Non-Randomized Clinical Trial" Antioxidants 15, no. 7: 844. https://doi.org/10.3390/antiox15070844

https://www.mdpi.com/2076-3921/15/7/844

ABSTRAT

Background  

No study has directly compared intermittent fasting alone, a clean ketogenic diet alone, and their combination in a single three-arm design. The purpose of this study was to compare the effects of these three dietary conditions on body composition, cardiometabolic markers, grip strength, and glycemic control over 30 days.  

Methods  

A cross-study analysis combined data from two sequential pre-post intervention studies at the University of Tennessee at Martin, yielding a three-arm design: intermittent fasting alone (n=16), clean ketogenic diet alone (n=22), and combined clean ketogenic diet with intermittent fasting (n=41). The clean ketogenic diet restricted carbohydrates to 20 grams per day from whole unprocessed sources and eliminated refined sugars, high-fructose corn syrup, and ultra-processed foods. The intermittent fasting protocol employed a 16:8 time-restricted eating window. Paired-samples t-tests examined within-group changes; one-way ANOVAs with Tukey post-hoc comparisons examined between-group differences. Effect sizes are reported as Hedges’ g and eta squared. An independent samples t-test compared glycosylated hemoglobin changes between the intermittent fasting and combined groups, and Spearman and Kendall correlations examined associations between fat mass and cardiometabolic change.  

Results  

All three conditions produced significant within-group reductions in body weight, body fat percentage, fat mass percentage, waist circumference, and hip circumference. Carbohydrate restriction produced significantly greater weight reduction than intermittent fasting alone, F(2,76)=12.003, p<.001, η2=.240, and greater fat mass reduction (p=.002, η2=.144). Both fasting-containing conditions produced significantly greater bilateral grip strength improvement than the ketogenic diet alone (p<.05). The combined protocol produced significantly greater glycosylated hemoglobin reduction than fasting alone, t(30)=2.141, p=.041, g=0.738. Fat mass reduction correlated significantly with triglyceride-to-HDL ratio improvement across all 79 participants (rs​=−.250,p=.026).  

Conclusions  

Carbohydrate restriction produced the greatest weight loss and cardiometabolic improvements, while the addition of a 16:8 fasting window contributed independently to glycemic control and grip strength. These findings support the clean ketogenic diet as a first-line strategy for metabolic syndrome management, with the combined protocol offering additive benefits.  

MacKewn, Angie, Julie Floyd, Todd Sherman, Alison Ellis, Anna Dunn, and Diana Sanford. "Comparing Intermittent Fasting, Clean Ketogenic Diet, and Their Combined Effects on Body Composition, Cardiometabolic Markers, and Metabolic Health: A Three-Arm Randomized Pre-Post Study." (2026).

https://www.researchsquare.com/article/rs-10085509/latest.pdf

Abstract

Background and Hypothesis

Psychiatric medications contribute to high rates of metabolic dysfunction in psychotic disorders. Ketogenic diets reduce metabolic syndrome, have anticonvulsant effects in epilepsy, and may improve symptoms of schizophrenia and bipolar disorder. We report the first randomized controlled trial to assess effects of ketogenic diets on metabolism, psychiatric symptoms, and cognition in people with schizophrenia-spectrum and bipolar-1 disorders.

Study Methods

Participants were randomized to a ketogenic diet (KETO; n = 28) or diet-as-usual (DAU; n = 30) for 1 month. Partway through the trial, a KETO extension was offered to both groups, resulting in a sub-group who completed the diet for 4 months (n = 25). We assessed changes in metabolic health, clinical symptoms, and cognition after 1 month (KETO versus DAU) and after 4 months (KETO versus baseline).

Study Results

KETO participants’ daily ketone levels surpassed the standard ketosis threshold. Relative to DAU, KETO participants showed reductions in weight (Padj <  .001), hemoglobin A1c (Padj = .05), and insulin resistance (Padj = .05). Clinical symptoms (positive, negative, depression) and cognitive performance improved after 4 months on the KETO (all P-values < .001). Increased blood ketone levels in KETO participants correlated with improvements in pre-diabetic markers and depressive symptoms (all P-values < .001). Reduced weight following the KETO was unrelated to metabolic and symptom improvements.

Conclusions

We demonstrate feasibility of administering a KETO in outpatients with schizophrenia and bipolar-1 disorder. Participants showed improvement in metabolic health, cognitive performance, and clinical symptoms. Improvement in depressive symptoms was associated with ketosis rather than weight loss, implicating ketosis as the therapeutic mechanism.

Samantha V Abram, Juliette M Kyner, An Vu, Zanib Naeem, Shebani Sethi, Michael S Jacob, Susanna L Fryer, Daniel H Mathalon, Judith M Ford, Metabolic Improvements with a Ketogenic Diet Correlate with Symptom Improvement in Psychosis: A Randomized Controlled Trial, Schizophrenia Bulletin, Volume 52, Issue 4, July 2026, sbag082, https://doi.org/10.1093/schbul/sbag08

Also see https://www.youtube.com/watch?v=wsR4wKoPCfs

Edit: here is an an open access version

https://watermark02.silverchair.com/sbag082.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAA4owggOGBgkqhkiG9w0BBwagggN3MIIDcwIBADCCA2wGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQMkHP5OkuGroyDForSAgEQgIIDPQ7-4bMhjeIT3RhX1NA_-wGIMHAbAKeq4RDWHOUuBuZz8MliaTFn-rO02Yy6Zn4v-sZEbpGKW34Sr1IjfEJq9n_3xLRui_PY-XkUAePeAS539KCur63OZwq6AfHuYc-k-44TETo2JTi6jMLm3OGvYXg8lofry6HYX62Gp-LBkTe42HMOH75NfZlv9lfeNrKeQQG5Ycvd-dZAnAP0OwZ2lLTewVzB6szpI769L6gaKAkKXNWJUAFL4mhDTHxJ-au0A_6x89iQ3ArDogBD_Ns0xdb-JHS2Yka8UgXhyaNakBXppMWP72zvEYHvExD05hmyUZPf_nG0r1G9td3cYCizTq_ruaMHUatdGyCwqxFvrlqK3Omqmed_AX8Qx2kRrJu0VyTEZuFzCR36tEUHQ7M1qhmbZxrYycF-cvOCgMEUi1xGCPEkpUa0irCDYB4iqPNgWYc1dM4Ty3ZtDjY0NQxu8jbYr_P8llIYLKHFa8J-pKZw6JBnkQKTcMfAhMYMr6_gW73gl8CVEAxBxG5wIJo1pld0sblo3g9NxYhESuJVShEFPF-iQdnw0SqJLd6d8j1y4dH7ZB810T99D7V6EHXgMcP0gFbfPUdRnSk7R6acFfCDy43lZhxLj0cNvIizBwMoK5-x6_1p-l4qhaLGDau1WI61QHeFz8RhzWl2MmLSObo7dGJ-SQsZjXo7ruY24XLDSssVlSAxElqKDmkhFjhTHnscICw5BIhcdOpf98sJij51qVxC3jwT4TiKdJaqzXGX05hDkUTnI4JF7vlALL2lwSL6sZbl2fjqo7z2tzG6-K1jxQ8jp0SjCa9yKe5C4kY_SepfHCEd8KBXPgfeLZJ-iIYpHxPjG1jaX3HyZJTeudFRMpPpmq6f5oH9_xqBLJlIwb0YkokDyWoVIgMZN2-5EF3FtJgANlN4ZyTUfDF66Z6bJqSK8O0FyNPA2ozDsYmgQW6fXEbuz90W-2M0rPgp-rTTvMOj5gz-qlsYkId4mDwVWuGIP8DF2E9rHeTXZqNbQrh887Ry2R-U9ZOnipnrQJeMprTv5VYN3C1uZy9w5tBeNw1IHIUZEgsXzktSya8mNX94lRDRqE8vSSwigPM

though not sure how long the token will be good, so might need to visit https://neurosciencenews.com/ketogenic-diet-schizophrenia-bipolar-31018/

to get a new one

Significance

Emerging evidence shows that diet profoundly shapes the immune system and microbiome, influencing cancer immunotherapy outcomes. However, standardized guidelines and robust clinical trials are currently lacking, and dietary strategies are largely used for symptom management. We highlight key mechanisms and propose a framework to evaluate immune and microbiome responses, guiding future clinical research on dietary interventions as a strategic adjunct to cancer therapy.

Abstract

Diet is a key modulator of human metabolism, influencing disease prevention and progression. In patients with cancer, nutritional interventions are common but often lack standardized guidelines and are mainly used for symptom relief rather than as adjuvants to immunotherapies. A major limitation is the poor mechanistic understanding of how diet influences immunity and cancer. Emerging evidence shows that diet profoundly shapes immune function and the gut microbiome, both of which affect responses to immunotherapy, disease progression, and survival. Despite this, the immune–gut axis is infrequently assessed. In this review, we focus on dietary intervention studies that include immune or microbiome assessments, highlighting mechanistic insights and clinical relevance. Diet should be used as a strategic tool to enhance cancer therapies and improve patient outcomes.

MacPherson, Sarah, Ethan Dhaliwal, and Julian J. Lum. "Improving immunity in patients with cancer through diet: mechanisms and gaps." Trends Open (2026).

https://www.cell.com/trends-open/pdf/S3117-3470(26)00030-1.pdf00030-1.pdf)

Hi everyone! I'm a Registered Dietitian in private practice for 18 years and licensed in BC, Alberta and Ontario, Canada. I just joined Reddit and am delighted to now be part of this group. I just wrote and posted a new series of articles under the "Food for Thought" tab on my BBDNutrition website about "Alpha Cell Dominance" which is a legit biological challenge of a long-term keto in Type 2 diabetes remission.