Daily Endocrinology Research Analysis
A first-in-class small molecule targeting the core circadian transcription factor BMAL1 demonstrates selective biochemical, structural, and cellular engagement with anti-inflammatory effects in macrophages. Large-scale adipose tissue transcriptomics link HbA1c to shifts in cellular composition and immune–ECM–senescence pathways, highlighting RHO GTPases as unrecognized glucose homeostasis correlates. In transgender health, a 2,095-person cohort on testosterone showed no observed cervical cancer
Summary
A first-in-class small molecule targeting the core circadian transcription factor BMAL1 demonstrates selective biochemical, structural, and cellular engagement with anti-inflammatory effects in macrophages. Large-scale adipose tissue transcriptomics link HbA1c to shifts in cellular composition and immune–ECM–senescence pathways, highlighting RHO GTPases as unrecognized glucose homeostasis correlates. In transgender health, a 2,095-person cohort on testosterone showed no observed cervical cancer and no increased high-grade CIN risk over short-term exposure, informing screening guidance.
Research Themes
- Circadian clock pharmacology and immunometabolism
- Adipose tissue transcriptomics and glycemic control
- Transgender health: testosterone therapy and cervical neoplasia risk
Selected Articles
1. Pharmacological targeting of BMAL1 modulates circadian and immune pathways.
This study introduces a selective small molecule (CCM) that binds the BMAL1 PASB domain to modulate BMAL1-CLOCK activity, shifting circadian oscillations and suppressing inflammatory/phagocytic pathways in macrophages. Structural and cellular data establish target engagement and functional consequences, opening a path to clock-directed immunometabolic therapeutics.
Impact: Provides the first validated chemical probe directly engaging BMAL1 with downstream functional effects, enabling pharmacological manipulation of the core clock and immune pathways. This could catalyze new therapeutic strategies across metabolic, inflammatory, and circadian disorders.
Clinical Implications: While preclinical, a selective BMAL1 modulator offers a blueprint for circadian-targeted therapies that could mitigate inflammation and potentially improve metabolic control; it also provides a tool to stratify clock-dependent responses.
Key Findings
- Discovery of CCM, a small molecule that binds and expands the BMAL1 PASB cavity, altering BMAL1 conformation and function.
- Selective target engagement validated by biochemical, structural, and cellular assays, enabling modulation of BMAL1-CLOCK activities.
- CCM dose-dependently shifts PER2-Luc circadian oscillations and downregulates inflammatory and phagocytic pathways in macrophages.
Methodological Strengths
- Integrated biochemical, structural, and cellular validation of target engagement and function.
- Demonstrated selective modulation of clock output and immune pathways with a defined tool compound.
Limitations
- Lack of in vivo efficacy/safety data to translate macrophage findings to organismal physiology.
- Scope limited to BMAL1 PASB domain; broader clock network effects and long-term adaptation remain untested.
Future Directions: Evaluate CCM (and analogs) in vivo for pharmacokinetics, target engagement, and efficacy in inflammatory and metabolic disease models; delineate tissue-specific and sex-specific clock–immune interactions.
2. Incidence of cervical intraepithelial neoplasia and cervical cancer in transmasculine and gender diverse individuals using testosterone: a retrospective, single-centre cohort study.
In 2,095 TMGD individuals on testosterone (median exposure 1.7 years), no cervical cancers were observed and CIN2+ incidence was not elevated versus expectation (SIR 0.53). While reassuring for short-term risk, interpretation is limited by short follow-up and missing HPV/screening data.
Impact: Provides the largest cohort to date linking testosterone exposure with cervical neoplasia outcomes, informing counseling and screening strategies in transgender care.
Clinical Implications: Short-term testosterone therapy in TMGD individuals does not appear to increase cervical cancer or CIN2+ risk; routine cervical screening should continue, with emphasis on long-term surveillance and HPV status documentation.
Key Findings
- Among 2,095 TMGD individuals on testosterone, zero cervical cancer cases were observed versus 0.30 expected.
- Five CIN2+ cases were observed versus 9.5 expected (SIR 0.53, 95% CI 0.19–1.17).
- Median testosterone exposure was 1.7 years (IQR 1.3–2.5); missing HPV and screening data and short exposure limit inference.
Methodological Strengths
- Large cohort with linkage to a national pathology registry and age-adjusted SIR analysis.
- Clear case definition for high-grade lesions (CIN2+).
Limitations
- Relatively short median exposure/follow-up (1.7 years) limits assessment of long-term cancer risk.
- Lack of HPV prevalence and cervical screening adherence data may bias incidence estimates.
Future Directions: Extend follow-up with HPV genotyping and screening adherence data to refine risk estimates; evaluate testosterone dose–duration effects and potential interaction with HPV vaccination.
3. Cellular composition and transcriptomics of subcutaneous adipose tissue linked to blood glycated haemoglobin.
In 901 subcutaneous adipose samples, higher HbA1c associated with fewer adipocytes, pericytes, and endothelial-related cells and with enrichment of senescence, telomere, and ECM pathways. RHO GTPases emerged as novel HbA1c-linked signals (with obesity-shaped sexual dimorphism), and HLA-DR, CCL13, S100A4 correlated strongly with HbA1c; findings replicated in independent cohorts.
Impact: Links glycemic control to specific adipose cellular shifts and immune–ECM–senescence pathways, nominating RHO GTPases and immune markers as potential targets and biomarkers for adipose dysfunction in T2DM.
Clinical Implications: Adipose transcriptomic signatures (e.g., HLA-DR, CCL13, S100A4) and RHO GTPase pathways may guide risk stratification and therapeutic development targeting adipose inflammation, ECM remodeling, and senescence in insulin resistance.
Key Findings
- Higher HbA1c associates with reduced adipocytes, smooth muscle, pericytes, and endothelial-related cells in subcutaneous adipose tissue.
- Pathways linked to HbA1c include cellular senescence, telomere biology, and extracellular matrix organization.
- RHO GTPases correlate with HbA1c (not previously linked to glucose homeostasis), with obesity-shaped sexual dimorphism; gene-level markers HLA-DR, CCL13, S100A4 strongly correlate with HbA1c.
- Results replicated in two independent validation cohorts, including longitudinal settings.
Methodological Strengths
- Large-scale bulk transcriptomics with cell deconvolution coupled to clinical HbA1c, validated in two independent cohorts.
- Consistent pathway- and gene-level signals across analyses, supporting robustness.
Limitations
- Primary analysis is cross-sectional, limiting causal inference despite longitudinal validation cohorts.
- Bulk RNA-seq with computational deconvolution may not fully capture rare cell states compared to single-cell approaches.
Future Directions: Single-cell multi-omics and spatial profiling to resolve cell-state dynamics; interventional studies to test whether modulating RHO GTPases, senescence, or ECM pathways improves glycemic control.