Weekly Endocrinology Research Analysis
This week in endocrinology featured high-impact translational and mechanistic studies. A genomic–phenotypic–functional integration produced a high-performance pathogenicity–severity classifier for MCT8 variants, directly improving diagnosis and trial stratification for a treatable rare endocrine transporter disorder. Mechanistic work uncovered a phosphorylation switch (CK2/GSK3–MLX) that stabilizes ChREBP–MLX heterotetramers to control carbohydrate/lipid programs, offering a druggable nutrient-s
Summary
This week in endocrinology featured high-impact translational and mechanistic studies. A genomic–phenotypic–functional integration produced a high-performance pathogenicity–severity classifier for MCT8 variants, directly improving diagnosis and trial stratification for a treatable rare endocrine transporter disorder. Mechanistic work uncovered a phosphorylation switch (CK2/GSK3–MLX) that stabilizes ChREBP–MLX heterotetramers to control carbohydrate/lipid programs, offering a druggable nutrient-sensing axis. Single-cell and spatial transcriptomics identified a Mincle–oncostatin M macrophage–fibroblast axis that restrains adipose fibrosis, nominating an immunometabolic target for obesity-related tissue remodeling.
Selected Articles
1. Mapping variants in thyroid hormone transporter MCT8 to disease severity by genomic, phenotypic, functional, structural and deep learning integration.
An integrative multi-cohort and multi-modal study linked MCT8 (SLC16A2) variant classes to survival and 24 of 32 clinical features, characterized seven functional domains, identified mild phenocopies in population cohorts, and produced a pathogenicity–severity AI classifier (AUC 0.91/0.86) across 8,151 variants—enabling standardized diagnosis and stratification for clinical care and trials.
Impact: Provides a generalizable, validated framework for interpreting variants in an actionable endocrine gene with direct implications for diagnosis, prognosis, and trial stratification in a rare but treatable disorder.
Clinical Implications: Incorporate the classifier into genetic diagnostic pipelines for SLC16A2/MCT8 to enable earlier diagnosis, standardized severity grading, counseling, and selection for therapeutic trials; note that therapeutic effectiveness did not vary by LoF category in this study.
Key Findings
- Genotype–phenotype maps linked variant classes to survival and 24/32 clinical features in MCT8 deficiency.
- A mild phenocopy from common MCT8 variants was detected in ~400,000 population participants.
- Seven critical functional domains of MCT8 were delineated, improving structural understanding.
- An AI-based pathogenicity–severity classifier predicted pathogenicity (AUC 0.91) and severity (AUC 0.86) for 8,151 variants.
2. MLX phosphorylation stabilizes the ChREBP-MLX heterotetramer on tandem E-boxes to control carbohydrate and lipid metabolism.
This mechanistic study identifies CK2 and GSK3 as MLX kinases and shows MLX phosphorylation on a conserved motif is required to assemble and stabilize ChREBP–MLX heterotetramers on ChoREs; high glucose-6-phosphate inhibits this phosphorylation, linking nutrient state to transcriptional control of carbohydrate and lipid metabolism and nominating the CK2/GSK3–MLX axis as a therapeutic target.
Impact: Uncovers a fundamental, druggable post-translational switch for a central nutrient-sensing transcriptional complex with broad implications for metabolic disease intervention (NAFLD, hypertriglyceridemia, diabetes).
Clinical Implications: Although preclinical, modulation of the CK2/GSK3–MLX phosphorylation axis could enable targeted attenuation of ChREBP-driven lipogenesis in metabolic liver disease; tissue-specific strategies and safety profiling are next steps.
Key Findings
- MLX phosphorylation at a conserved motif is necessary for ChREBP–MLX heterotetramer assembly on ChoREs and downstream transcriptional activity.
- CK2 and GSK3 act as MLX kinases that stabilize heterotetramer formation.
- High intracellular glucose-6-phosphate inhibits MLX phosphorylation, linking nutrient flux to transcriptional control.
3. Novel Cell-to-Cell Communications Between Macrophages and Fibroblasts Regulate Obesity-Induced Adipose Tissue Fibrosis.
Using single-cell and spatial transcriptomics in diet-induced obese mice and human tissue correlations, the study identifies a Mincle+ macrophage subcluster localized to crown-like structures that induces oncostatin M (OSM) to suppress collagen gene expression in adjacent fibroblasts; immune-cell Osm deficiency exacerbates adipose fibrosis in vivo, nominating the Mincle–OSM axis as an immunometabolic brake on fibrosis.
Impact: Defines a previously unrecognized macrophage–fibroblast signaling axis that modulates obesity-associated adipose fibrosis, integrating single-cell, spatial, in vivo, and human validation—offering a tangible anti-fibrotic target in metabolic disease.
Clinical Implications: Targeting the Mincle–OSM pathway could be explored to limit adipose fibrosis and its metabolic sequelae; MINCLE/OSM expression in adipose biopsies might serve as biomarkers to stratify fibrotic risk in obese patients.
Key Findings
- Identified a Mincle+ macrophage subcluster localized to crown-like structures in obese adipose tissue.
- Mincle signaling upregulated oncostatin M, which suppressed collagen gene expression in fibroblasts.
- Immune-cell Osm deficiency enhanced adipose tissue fibrosis in vivo; MINCLE–OSM expression correlated in human adipose tissue.