Ontosight Newsletter Issue 25

Ontosight® - Biweekly Newsletter

April 21st 2025 - May 4th, 2025 - Issue 25

Welcome to the 25th edition of Ontosight® Newsletter! This issue features advancements in cancer immunotherapy, neurodegeneration, gut microbiota, cardiometabolic health, and novel therapeutics. Discover promising strategies to overcome immunotherapy resistance, insights into sex-specific Alzheimer’s pathology, and the gut’s role in systemic diseases. Plus, explore global regulatory highlights including key drug approvals for Alzheimer’s, cancer, and rare diseases.

Featured Articles

1. Cancer Biology & Immunotherapy

• Targeting VSIG4(+) tissue-resident macrophages enhances T cell cytotoxicity and immunotherapy efficacy in cancer

This study identified a tissue-resident macrophage-derived tumor-associated macrophage (TAM) subpopulation marked by VSIG4 overexpression in testicular and other cancers. These VSIG4+ TAMs suppress CD8+ T-cell immunity and are linked to poor prognosis. The transcription factor MEF2C regulates their activity. Targeting VSIG4 or MEF2C enhanced immune checkpoint therapy effectiveness in preclinical models. Read More

• Lysine-specific demethylase 1 deletion reshapes tumour microenvironment to overcome resistance to PD-1 therapy

This study reveals that LSD1 overexpression in hepatocellular carcinoma (HCC) is linked to poor prognosis and resistance to PD-1 blockade. LSD1 deletion enhances PD-L1 expression, boosts CD8+ T cell activity, and suppresses tumor growth. Combining LSD1 inhibition with anti-PD-1 therapy prevents tumor relapse and remodels the tumor microenvironment. These findings support this combination as a promising strategy to overcome immunotherapy resistance in advanced HCC. Read More

• Selective inhibition of canonical STAT3 signaling suppresses K-ras mutant lung tumorigenesis

This study demonstrates that inhibiting STAT3 with TTI-101 reduces tumor burden and enhances immune activation in a K-ras mutant lung adenocarcinoma (KM-LUAD) mouse model. TTI-101 improved dendritic cell and Th1 infiltration, suppressed pro-tumor STAT3 signaling, and boosted anti-tumor NF-κB pathways. These findings suggest STAT3 as a key driver of tumor-promoting inflammation and a promising therapeutic target in early-stage KM-LUAD. Read More

• Saikosaponin A induces cellular senescence in triple-negative breast cancer via PI3K/Akt inhibition

This study highlights Saikosaponin A (SSA), a low-toxicity natural compound, as an effective agent against breast cancer by inducing cellular senescence. SSA inhibited tumor cell proliferation, triggered cell cycle arrest, and suppressed the PI3K/Akt pathway via ROS generation. In vivo, SSA reduced tumor growth with minimal toxicity, suggesting its potential as a novel breast cancer therapy. Read More

• Quercetin Induces Apoptosis Through Downregulating P4HA2 and Inhibiting the PI3K/Akt/mTOR Axis in Hepatocellular Carcinoma

This study shows that quercetin induces apoptosis and inhibits growth in hepatocellular carcinoma (HCC) cells by downregulating P4HA2. Suppression of P4HA2 enhances quercetin’s pro-apoptotic effects. The PI3K/Akt/mTOR pathway is also involved in this mechanism, suggesting that quercetin exerts its antitumor activity in HCC through both P4HA2 inhibition and pathway suppression. Read More

2. Neurodegeneration & Mental Health

• Unraveling sex differences in Alzheimer's disease and related endophenotypes with brain proteomes

This study analyzed brain proteomes from 770 donors to investigate sex differences in Alzheimer's disease (AD). It identified numerous proteins linked to AD and its features, with 10 showing significant sex-by-trait interactions. These proteins are involved in functions like estrogen response and inflammation. The findings suggest potential sex-specific biomarkers for AD that warrant further investigation. Read More

• Hippocampal GPR35 is involved in depression-like behaviors induced by inflammation and mediates the antidepressant effects of fluoxetine

This study explored the role of GPR35 in inflammation-induced depression using an LPS-treated mouse model. Elevated GPR35 expression was linked to depressive-like behaviors, which were alleviated by inhibiting or knocking down GPR35. Activation of GPR35 worsened symptoms, while fluoxetine reduced its expression. These findings suggest GPR35 as a promising target for antidepressant therapy. Read More

• Increased sedentary behavior is associated with neurodegeneration and worse cognition in older adults over a 7-year period

This study examined the impact of sedentary behavior on brain health in older adults over seven years. Greater sedentary time was linked to smaller AD-related brain structures and worse cognitive performance, with faster hippocampal decline over time. These effects were more pronounced in APOE-ε4 carriers, highlighting sedentary behavior as a modifiable risk factor for Alzheimer's disease. Read More

• Effectiveness and safety of single anti-seizure medication as adjunctive therapy for drug-resistant focal epilepsy

This meta-analysis of 53 RCTs assessed the effectiveness and safety of 17 anti-seizure medications (ASMs) as adjunctive therapy for drug-resistant focal epilepsy. Topiramate, tiagabine, oxcarbazepine, and levetiracetam emerged as the most effective, with tiagabine ranking highest. However, some ASMs, particularly topiramate and oxcarbazepine, were linked to higher rates of somnolence. Further studies are needed to clarify safety profiles. Read More

3. Gut Microbiota, Metabolism & Systemic Disease

• Restoration of intestinal secondary bile acid synthesis: A potential approach to improve pancreatic β cell function in type 1 diabetes

This study reveals that type 1 diabetes (T1D) is linked to reduced gut microbial diversity and impaired secondary bile acid metabolism. Targeted microbiome interventions safely improved glycemic control, reduced insulin needs, and lowered inflammation. Responders showed enhanced beneficial bacteria, bile acid levels, and C-peptide responses. These findings support gut microbiome modulation as a potential T1D therapy. Read More

• Comprehensive analysis of gut microbiota and fecal metabolites in patients with autism spectrum disorder

This study explored gut microbiota and fecal metabolites in ASD patients using long-read 16S rRNA sequencing and metabolomics. While overall microbial diversity was similar to controls, specific bacterial taxa and metabolites, including dopamine and various amino/organic acids, differed significantly. These findings suggest gut microbiota and metabolites may serve as potential biomarkers and therapeutic targets in ASD. Read More

• Embelin improves alcoholic steatohepatitis via ATF6-mediated P2X7r-NLRP3 signaling pathway

This study shows that Embelin (EB), a natural compound, alleviates alcohol-associated liver disease (ALD) by reducing lipid accumulation and liver inflammation. EB modulates the ATF6–P2×7r/NLRP3 signaling pathway, suppressing inflammasome activation and pyroptosis. Loss of ATF6 reverses EB's protective effects, highlighting its regulatory role. These findings position EB as a potential therapeutic agent for ALD. Read More

4. Cardiometabolic & Vascular Health

• Association between biological aging and cardiovascular health

This study found that biological aging metrics, especially phenotypic age (PA), are strongly associated with cardiovascular disease (CVD) prevalence and mortality risk. Sleep duration may moderate these associations, potentially reducing their impact. Among the metrics, PA showed the best predictive ability for CVD, highlighting its clinical potential. Read More

• Post-procedural plasma D-dimer level may predict futile recanalization in stroke patients

This study found that high post-procedural d-dimer levels and a significant increase in d-dimer after endovascular treatment (EVT) are independently associated with poor functional outcomes (futile recanalization) in acute ischemic stroke patients. Monitoring d-dimer may help predict EVT effectiveness. Read More

• Frailty and cardiovascular safety of JAK inhibitors versus TNF inhibitors in rheumatoid arthritis

This retrospective study compared cardiovascular event (CVE) risks in rheumatoid arthritis patients treated with Janus kinase inhibitors (JAKis) versus tumor necrosis factor inhibitors (TNFis). Results showed no significant difference in CVE, major adverse cardiovascular events (MACE), or thromboembolic event (TE) risk between the two treatments. However, patient frailty strongly increased CVE risk, highlighting that individual patient profiles influence cardiovascular outcomes more than the choice of DMARD therapy. Read More

5. Pharmacology, Clinical Trials & Therapeutics

• Effectiveness and safety of teclistamab for relapsed or refractory multiple myeloma: a systematic review and meta-analysis

A systematic review and meta-analysis evaluated the effectiveness and safety of teclistamab, a bispecific antibody targeting BCMA and CD3, in patients with relapsed or refractory multiple myeloma. The study found that teclistamab demonstrated significant antitumor activity with an acceptable safety profile. These findings suggest that teclistamab is a promising treatment option for patients with relapsed or refractory multiple myeloma. Read More

• Bedtime vs Morning Antihypertensive Medications in Frail Older Adults

The BedMed-Frail randomized clinical trial assessed whether taking antihypertensive medications at bedtime, compared to morning intake, affects cardiovascular outcomes in frail older adults. The study found no significant difference in cardiovascular events between the two groups, suggesting that the timing of antihypertensive medication (morning vs. bedtime) does not impact cardiovascular outcomes in this population. Read More

• Lipid-Lowering Effect and Safety of Ezetimibe and Atorvastatin in Primary Hypercholesterolemia

This Phase 3 clinical trial evaluated ezetimibe combined with low-dose atorvastatin (5 mg) in patients with high cholesterol. The combination significantly lowered LDL-C levels compared to atorvastatin alone. It showed a safety profile similar to monotherapy. The results support its use for better cholesterol control with fewer side effects. Read More

Additional Highlights

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

• Nuciferine ameliorates blood-brain barrier disruption post-ischemic stroke via inhibiting the JAK2/STAT3 pathway

• Embelin improves alcoholic steatohepatitis in alcohol-associated liver disease via ATF6-mediated P2X7r-NLRP3 signaling pathway

• Enhanced IL36RN Expression and Its Association With Immune Microenvironment Predicts Poor Prognosis in Gastric Cancer

• Fixed-duration Calquence-based regimens recommended for approval in the EU by CHMP for 1st-line chronic lymphocytic leukaemia

• CHMP recommends EU label update for Roche’s Phesgo to allow administration outside of clinical settings