Ontosight Newsletter Issue 27

Ontosight® - Biweekly Newsletter

June 02nd, 2025 - June 15th, 2025 - Issue 27

Welcome to the 27th edition of the Ontosight® Newsletter! This issue highlights advances in aging, cardiometabolic health, cancer, neuroscience, and infectious diseases. Discover breakthroughs in senescence therapies, gut-brain signaling, precision oncology, and AI-driven drug development, along with recent regulatory approvals.

Featured Articles

1. Cancer Research

• Immune targeting of triple-negative breast cancer through a clinically actionable STING agonist-CAR T cell platform

This study presents a novel strategy to treat triple-negative breast cancer (TNBC) by combining STING agonists with CAR T cell therapy. Using an FDA-approved PEG marker for localized delivery, researchers overcame STING-related T cell toxicity and achieved complete tumor eradication in mice. The approach offers a promising and translatable cancer immunotherapy platform for TNBC and other solid tumors. Read More

• MET pathway inhibition increases chemo-immunotherapy efficacy in small cell lung cancer

This study highlights that adding a MET inhibitor to existing chemo-immunotherapy significantly enhances treatment for small cell lung cancer (SCLC) by reducing tumor growth and reshaping the tumor microenvironment. Elevated HGF/MET pathway activity and myeloid cell infiltration are linked to resistance, but targeting this pathway boosts immune response and survival. These findings support MET inhibition as a promising strategy to improve outcomes in specific, biomarker-defined SCLC patients. Read More

• Transduction of γδ T cells with Baboon envelope pseudotyped lentiviral vector encoding chimeric antigen receptors for translational and clinical applications

This study introduces an improved method to enhance CAR expression in γδ T cells using a Baboon-pseudotyped lentiviral vector (BaEV-LV), greatly boosting their anti-tumor activity. These engineered cells showed superior cytotoxicity against B7H3-expressing tumors in both 2D and 3D models. The method is also GMP-compatible, enabling efficient, clinical-grade production and advancing the potential of γδ T cell-based therapies for solid tumors. Read More

• A dual-targeting strategy to inhibit colorectal cancer liver metastasis via tumor cell ferroptosis and cancer-associated fibroblast reprogramming

This study targets colorectal cancer (CRC) liver metastasis using a dual-targeted nanosystem that simultaneously induces ferroptosis in tumor cells and reprograms cancer-associated fibroblasts (CAFs). By leveraging cancer and CAF membranes for delivery, the approach disrupts both tumor and microenvironment, effectively suppressing tumor growth and enhancing immune response in advanced mouse models. It demonstrates a promising therapeutic strategy for tackling aggressive CRC metastasis. Read More

• A novel mitochondrial autophagy and aging-related gene signature for predicting ovarian cancer

This study identified 52 mitochondrial autophagy and aging (MiAg)-related genes differentially expressed in ovarian cancer and developed a 5-gene MiAgscore to stratify patients into high- and low-risk groups. The MiAgscore reliably predicted survival, with lower scores linked to better outcomes. These findings offer a potential biomarker-based approach for personalized prognosis and therapy in OC. Read More

2. Neuroscience & Mental Health

• The immunoproteasome disturbs neuronal metabolism and drives neurodegeneration in multiple sclerosis

This study reveals that in multiple sclerosis (MS), inflammation triggers overexpression of the immunoproteasome subunit PSMB8, disrupting normal protein degradation in neurons. This leads to buildup of the metabolic enzyme PFKFB3, causing oxidative stress, energy imbalance, and ferroptosis. Targeting PSMB8 or PFKFB3 offers a promising strategy to protect neurons and develop new neuroprotective therapies.. Read More

• Ciliatoside A attenuates neuroinflammation in Alzheimer's disease by activating mitophagy and inhibiting NLRP3 inflammasome activation

This study highlights the dual therapeutic potential of Ciliatoside A (CA), a natural compound, in Alzheimer’s disease by inhibiting NLRP3 inflammasome-mediated neuroinflammation and promoting mitophagy. CA improved mitochondrial health, reduced oxidative stress, and enhanced cognitive function in cellular, worm, and mouse models. It acts via the AMPK/ULK1 and PINK1/Parkin pathways, offering a promising approach to slow AD progression. Read More

• Integrative fMRI and multiomics reveal neuroprotective mechanisms of Astragalus membranaceus in sleep deprivation-induced depression

This study shows that Astragalus membranaceus (AST) alleviates sleep deprivation-induced depression-like behavior by restoring gut microbiota, reducing neuroinflammation, and improving brain function. Using a multiomics approach in mice, AST was found to rebalance gut-brain axis signaling, enrich beneficial microbes, and restore metabolic and inflammatory homeostasis. These findings highlight AST’s potential as a treatment for neuropsychiatric effects of sleep deprivation. Read More

• Arbutin ameliorated depression by inhibiting neuroinflammation and modulating intestinal flora

This study investigated the antidepressant effects of arbutin (AR) in a mouse model of depression. AR alleviated depressive-like behaviors by reducing neuroinflammation and oxidative stress, restoring neurotrophic and gut barrier functions, and modulating the gut microbiota and tryptophan metabolism. These effects were linked to the TLR4/NF-κB/IRAK1 pathway and AR’s interaction with serotonin-related enzymes TPH1 and IDO1. Read More

• Efficacy and tolerability of pharmacological interventions for schizophrenia non-responsive to prior treatment: a systematic review and network meta-analysis

This study systematically reviewed 150 RCTs involving 11,375 patients to compare pharmacological treatments for treatment-resistant schizophrenia (TRS). Clozapine emerged as the most effective option, especially for overall and positive symptoms, with certain combination therapies offering additional benefits. However, most estimates had low confidence, highlighting the need for personalized treatment and further research on non-clozapine combinations and long-term outcomes. Read More

3. Cardiovascular & Metabolic Health

• Association between the dietary index for gut microbiota and cardiometabolic multimorbidity: systemic immune-inflammation index and systemic inflammatory response index

This study found that a higher Dietary Index for Gut Microbiota (DI-GM) is linked to a lower risk of cardiometabolic multimorbidity (CMM), partly through reduced systemic inflammation. Inflammatory markers SII and SIRI were shown to mediate this relationship. The protective effect was stronger among individuals with higher education levels. These findings suggest that gut microbiota-targeted nutrition may help prevent or manage CMM. Read More

• Association of neutrophil/high-density lipoprotein cholesterol ratio with the cardiovascular-kidney-metabolic syndrome and its cardiovascular mortality

This study found that a higher neutrophil-to-HDL cholesterol ratio (NHR) is significantly associated with a greater prevalence of cardiovascular-kidney-metabolic (CKM) syndrome and increased cardiovascular mortality. NHR showed a positive linear trend with both CKM syndrome risk and CVD mortality. These findings suggest NHR could serve as a useful biomarker for early detection and prognosis in CKM syndrome. Read More

• Endothelial soluble epoxide hydrolase links polyunsaturated fatty acid metabolism to oxidative stress and atherosclerosis progression

This study reveals that endothelial cells with elevated soluble epoxide hydrolase (sEH) promote atherosclerosis by producing a DHA metabolite that disrupts mitochondrial function, increases oxidative stress, and triggers pro-inflammatory pathways. Endothelial-specific sEH overexpression accelerates plaque formation, while its deletion protects against it. Targeting sEH and PUFA metabolism in the endothelium may offer new vascular protective strategies. Read More

• Empagliflozin restores cardiac metabolism and suppresses immune activation in acute myocardial infarction

This study shows that Empagliflozin (EMPA) restores cardiac energy metabolism and reduces harmful metabolites such as UDP-glucose and GM3 gangliosides after acute myocardial infarction (AMI), independent of diabetes status. EMPA also decreases immune cell infiltration and cardiac tissue damage. These combined metabolic and immunomodulatory effects contribute to long-term cardioprotective benefits post-AMI. Read More

4. Aging & Longevity

• Senescence-resistant human mesenchymal progenitor cells counter aging in primates

This study developed senescence-resistant human mesenchymal progenitor cells (SRCs) to counteract aging. In a 44-week trial in aged macaques, intravenous SRCs reduced cellular senescence, chronic inflammation, and tissue degeneration, with no adverse effects. The treatment also improved brain structure, cognitive function, and reproductive health, partly through exosome-mediated anti-senescence effects. These findings highlight SRCs as a potential regenerative therapy for age-related decline. Read More

• Metabolic analysis of sarcopenic muscle identifies positive modulators of longevity and healthspan in C. elegans

This study identified age-related changes in skeletal muscle metabolites and tested their effects on aging and neurodegeneration using C. elegans models. Four metabolites—beta-alanine, 4-guanidinobutanoic acid, 4-hydroxyproline, and pantothenic acid—were found to enhance lifespan, healthspan, and mitochondrial health. These metabolites also showed benefits in models of ALS and DMD. Findings highlight muscle-derived metabolites as potential therapeutics for aging and neuromuscular diseases. Read More

• FGF21 promotes longevity in diet-induced obesity through metabolic benefits independent of growth suppression

This study shows that overexpressing FGF21 in fat tissue starting in adulthood improves metabolism and extends lifespan in mice on a high-fat diet. Treated mice resisted weight gain, had better insulin sensitivity, and reduced liver fat and inflammation. Benefits occurred even without adiponectin, suggesting fat tissue as a key target for FGF21. Findings highlight FGF21's therapeutic potential for metabolic syndrome and age-related diseases. Read More

5. Machine Learning & Precision Medicine

• Identification of key genes in membranous nephropathy and non-alcoholic fatty liver disease by bioinformatics and machine learning

This study found that membranous nephropathy (MN) may contribute to non-alcoholic fatty liver disease (NAFLD) through immune and inflammatory pathways. By analyzing gene expression data, the researchers identified CSF1R as a key shared gene between MN and NAFLD. CSF1R may serve as a potential therapeutic target for patients with both conditions. Read More

• Identifying early blood glucose trajectories in sepsis linked to distinct long-term outcomes: a K-means clustering study with external validation

This study identified five distinct early blood glucose (BG) trajectory patterns in sepsis patients, with high or unstable BG trends linked to increased 1-year mortality. Patients with stable low-to-moderate BG had the lowest risk, while external validation confirmed these findings. Optimal glucose control (122-160 mg/dL) and low glycemic variability improved survival, highlighting the value of dynamic BG monitoring for prognosis and personalized treatment in sepsis. Read More

• Two-Sample Network Mendelian Randomization and Single-Cell Analysis Reveal the Causal Associations and Underlying Mechanisms Between Antihypertensive Drugs and Kidney Cancer

This study used multi-omics and causal inference to evaluate how 12 antihypertensive drug classes affect kidney cancer risk. It found that calcium-channel blockers and vasodilators may reduce risk, while ACE inhibitors may increase it. Key genes like CACNA1C, CALM1, ACE, and LTA4H were identified as mediators. These findings support personalized antihypertensive therapy for cancer prevention. Read More

• The association of obesity and lipid-related indicators with all-cause and cardiovascular mortality risks in patients with diabetes or prediabetes: a cross-sectional study based on machine learning algorithms

This study assessed eight obesity and lipid-related indicators, finding that TyG, TyG-WWI, and ABSI are significantly linked to increased all-cause and cardiovascular mortality in patients with diabetes or prediabetes. TyG had the strongest predictive value, especially for cardiovascular risk. Machine learning models, particularly XGBoost, validated these indicators' importance in mortality prediction. Read More

6. Infectious Diseases & Immunology

• Emerging tick-borne diseases in mainland China over the past decade: a systematic review and mapping analysis

This study provides a systematic review and mapping analysis of emerging tick-borne diseases in mainland China from 2015 to 2025, identifying 28 diseases linked to diverse pathogens with distinct regional patterns. Clinical presentations were mainly febrile and nonspecific, highlighting diagnostic challenges. The widespread detection of pathogens in 40 tick species suggests underdiagnosis and emphasizes the need for improved surveillance and public health strategies. Read More

• ILC3s sense gut microbiota through STING to initiate immune tolerance

This study identifies STING signaling in group 3 innate lymphoid cells (ILC3s) as a key mechanism for establishing immune tolerance to gut microbiota. STING enables ILC3s to present antigens, migrate to lymph nodes, and promote microbiota-specific regulatory T cells. However, excessive STING activation during inflammation leads to ILC3 death, disrupting gut immune balance. Read More

• Evolution of ceftazidime-avibactam resistance driven by variation in bla KPC-2 to bla KPC-190 during treatment of ST11-K64 hypervirulent Klebsiella pneumoniae

This study identifies and characterizes a novel Klebsiella pneumoniae carbapenemase variant, KPC-190, found in a hypervirulent ST11-K64 strain during ceftazidime-avibactam (CZA) treatment. KPC-190 confers high-level CZA resistance while partially restoring carbapenem susceptibility through altered enzyme kinetics and avibactam evasion. Its plasmid-mediated mobility and virulence potential underscore the need for vigilant genomic surveillance and alternative therapeutic strategies. Read More

Additional Highlights

Explore more groundbreaking research and regulatory updates in our biweekly newsletter:

• Mitochondria-targeted therapy with metformin and MitoQ reduces oxidative stress, improves mitochondrial function, and restores metabolic homeostasis in a murine model of Gulf War Illness

• Caged-hypocrellin mediated photodynamic therapy induces chromatin remodeling and disrupts mitochondrial energy metabolism in multidrug-resistant Candida auris

• Vitamin C improves 28-day survival in patients with sepsis-associated acute kidney injury in the intensive care unit: a retrospective study

• iPSC-derived trimodal T cells engineered with CAR, TCR, and hnCD16 modalities can overcome antigen escape in heterogeneous tumors

• ImmunityBio Receives FDA Expanded Access Authorization for Landmark Treatment of Lymphopenia With ANKTIVA®, the Cancer BioShield™ Platform, in Patients With Solid Tumors

• U.S. FDA Grants Platform Technology Designation to the Viral Vector Used in SRP-9003, Sarepta’s Investigational Gene Therapy for the Treatment of Limb Girdle Muscular Dystrophy Type 2E/R4

• Gilead Provides Update on Clinical Studies Evaluating GS-1720 and/or GS-4182 for the Treatment of HIV-1 Infection

• Outlook Therapeutics® Announces Commercial Launch of LYTENAVA™ (bevacizumab gamma) in Germany and the UK for the Treatment of Wet AMD

• China’s Center for Drug Evaluation Accepts Merck’s Application for Marketing Authorization of Pimicotinib for Treatment of Tenosynovial Giant Cell Tumor