Daily Endocrinology Research Analysis
Three impactful studies advance metabolic and endocrine science across the MASLD/MASH spectrum and type 2 diabetes therapy. A translational Hepatology paper identifies neutrophil proteases NE/PR3, regulated by the miR-223/STAT3 axis, as drivers of MASH fibrosis; a large multicenter Gastroenterology cohort defines a dynamic “burning-out” steatosis phenotype linked to worse outcomes; and a randomized trial shows imeglimin significantly lowers HbA1c when added to DPP-4 inhibitors.
Summary
Three impactful studies advance metabolic and endocrine science across the MASLD/MASH spectrum and type 2 diabetes therapy. A translational Hepatology paper identifies neutrophil proteases NE/PR3, regulated by the miR-223/STAT3 axis, as drivers of MASH fibrosis; a large multicenter Gastroenterology cohort defines a dynamic “burning-out” steatosis phenotype linked to worse outcomes; and a randomized trial shows imeglimin significantly lowers HbA1c when added to DPP-4 inhibitors.
Research Themes
- Immunometabolic drivers of steatohepatitis and fibrosis
- Dynamic risk phenotyping in MASLD (burning-out steatosis)
- Adjunctive pharmacotherapy (imeglimin) in T2D on DPP-4 inhibitors
Selected Articles
1. Neutrophil serine proteases NE and PR3 controlled by the miR-223/STAT3 axis potentiate MASH and liver fibrosis.
Human MASH livers show marked increases in neutrophil proteases NE and PR3 that correlate with histologic severity. Genetic deletion or AAV-mediated inhibition of NE/PR3 mitigated steatohepatitis and fibrosis in mice, while miR-223 suppresses NE/PR3 via STAT3; miR-223 deficiency exacerbated disease. Bone marrow chimerism experiments indicate hematopoietic miR-223 regulates hepatic NE/PR3 and fibrosis progression.
Impact: Identifies neutrophil proteases as causal immunometabolic drivers of MASH fibrosis under miR-223/STAT3 control, defining druggable targets (NE, PR3) with strong human–mouse translational evidence.
Clinical Implications: Supports development of NE/PR3 inhibitors and strategies to boost miR-223 signaling as potential anti-fibrotic therapies in MASH. Biomarker work on NE/PR3 could inform risk stratification.
Key Findings
- NE and PR3 were markedly increased in human MASH/fibrotic livers and correlated with histology.
- Genetic ablation or AAV-mediated inhibition of NE/PR3 reduced steatohepatitis and fibrosis in mice.
- miR-223 suppressed neutrophilic NE/PR3 by targeting STAT3; miR-223 deficiency worsened inflammation/fibrosis.
- Bone marrow transplantation generating miR-223 chimerism modulated hepatic NE/PR3 and MASH fibrosis progression.
Methodological Strengths
- Human–mouse translational design with 121 human liver biopsies and multiple genetic/viral perturbations.
- Mechanistic dissection of the miR-223/STAT3 axis with bone marrow chimerism to pinpoint hematopoietic contribution.
Limitations
- Predominantly preclinical efficacy; no human interventional data yet.
- Diet-induced mouse models may not capture full MASLD/MASH heterogeneity.
Future Directions: Test NE/PR3 inhibitors or miR-223–modulating therapies in clinically relevant models and early-phase trials; validate NE/PR3 as biomarkers for activity and response.
BACKGROUND AND AIMS: Metabolic dysfunction-associated steatohepatitis (MASH) and its related liver fibrosis represent a substantial public health burden with limited treatment options. Although MASH is associated with enhanced neutrophil infiltration in the liver, the mediators and mechanisms underlying neutrophil-driven progression of MASH and fibrosis remain largely unknown. This study aimed to investigate the role of neutrophil serine proteases neutrophil elastase (NE) and proteinase 3 (PR3) in the development of MASH and fibrosis. APPROACH AND RESULTS: Liver biopsies from 121 morbidly obese patients were recruited for analysis. NE -/- , PR3 -/- , microRNA-223 (miR-223) -/- mice and their wild-type controls were fed a choline-deficient, l -amino acid-defined, high-fat diet to induce MASH fibrosis. Bone marrow transplantation was performed to generate mice with miR-223 chimerism in bone marrow-derived cells. NE and PR3 content in the human liver with MASH and fibrosis was markedly increased in close association with histological features. Genetic ablation or adeno-associated virus-mediated inhibition of NE and PR3 substantially alleviated MASH and liver fibrosis in mice. A mechanistic study revealed that miR-223 suppressed neutrophilic NE and PR3 by targeting signal transducer and activator of transcription 3. MiR-223 deficiency augmented inflammation and fibrosis in mouse liver. Bone marrow transplantation-induced miR-223 chimerism significantly affected hepatic NE/PR3 content and the progression of MASH fibrosis in mice. CONCLUSIONS: Our findings reveal that NE and PR3 are key factors triggering liver inflammation to potentiate the development of MASH and liver fibrosis, offering insight into the development of new therapeutic approaches that target NE and PR3.
2. From "Burnt-Out" to "Burning-Out": Capturing Liver Fat Loss in Patients With Advanced Metabolic Dysfunction-Associated Steatotic Liver Disease From a Dynamic Perspective.
In a 16-center cohort (n=3273 histology; n=5455 serial VCTE), ‘burnt-out’ MASLD (≤S1 steatosis, ≥F3 fibrosis) carried significantly higher risks of mortality, liver-related events, and decompensation. Trajectory-defined ‘burning-out’ MASLD, with progressive CAP decline and LSM rise, also showed elevated adverse outcome rates, underscoring that fat loss in advanced disease signals worse prognosis.
Impact: Establishes a dynamic steatosis-loss phenotype (‘burning-out’) linked to adverse outcomes, challenging reliance on steatosis as a benign sign in advanced MASLD and informing risk stratification.
Clinical Implications: Patients with advanced MASLD and low/declining steatosis merit aggressive surveillance for decompensation and liver-related events; dynamic CAP/LSM trajectories can refine prognosis and therapeutic prioritization.
Key Findings
- Defined ‘burnt-out’ MASLD (≤S1 steatosis, ≥F3 fibrosis) in 435/3273 histology cases with higher mortality (HR 2.14), LREs (HR 1.77), and decompensation (HR 1.83).
- Identified 176 ‘burning-out’ patients via trajectory analysis (falling CAP, rising LSM) with elevated incidence of adverse outcomes.
- Burning-out group had higher cumulative incidence of events than patients with consistently high CAP and lower LSM (P < .0001).
Methodological Strengths
- Very large, multicenter cohort integrating histology and longitudinal elastography.
- Trajectory-based phenotyping capturing dynamic disease behavior beyond static snapshots.
Limitations
- Observational design susceptible to residual confounding.
- Definitions rely on CAP/LSM thresholds which may vary by device/setting.
Future Directions: Prospective validation of burning-out trajectories across platforms and integration into risk models; evaluate whether targeted antifibrotic or metabolic therapies alter burning-out course.
BACKGROUND & AIMS: The absence of hepatic fat in advanced fibrosis has been documented in metabolic dysfunction-associated steatotic liver disease ("burnt-out" MASLD). However, whether hepatic fat loss occurs continuously with fibrosis progression is controversial. We proposed a "burning-out" concept to describe this process and analyze the long-term outcomes of "burnt-out" and "burning-out" MASLD. METHODS: We included a MASLD cohort from 16 centers, including 3273 individuals with baseline histology and 5455 with serial vibration-controlled transient elastography measurements during the follow-up. "Burnt-out" MASLD was defined by steatosis grade ≤S1 and fibrosis stage ≥F3. Trajectory analysis identified "burning-out" patients with continuous trends of decreasing controlled attenuation parameter and increasing liver stiffness measurement values. RESULTS: Of 3273 patients with histologic evaluation included, 435 had "burnt-out" MASLD. Compared with those with pronounced steatosis in advanced fibrosis, patients with "burnt-out" had higher risks of all-cause mortality (hazard ratio [HR], 2.14; 95% confidence interval [CI], 1.14-4.02), liver-related events (LREs; HR, 1.77; 95% CI, 1.12-2.78), and hepatic decompensation (HR, 1.83; 95% CI, 1.11-3.01). Of 5455 patients with vibration-controlled transient elastography included for trajectory analysis, 176 were identified as "burning-out" MASLD. The incidence rates of all-cause mortality, LREs, and decompensation were 7.28, 26.47, and 21.92 per 1000 person-years in "burning-out" patients, respectively. The "burning-out" group had higher cumulative incidences of adverse outcomes than patients with consistently high controlled attenuation parameter and moderate/low liver stiffness measurement values (P < .0001). CONCLUSIONS: Continuous hepatic fat loss accompanied by fibrosis progression, referred to as "burning-out," was observed in advanced MASLD and associated with high rates of all-cause mortality, LREs, and hepatic decompensation.
3. Efficacy and safety of imeglimin add-on to DPP-4 inhibitor therapy in Japanese patients with type 2 diabetes mellitus: An interim analysis of the randomised, double-blind FAMILIAR trial.
In this randomized, double-blind interim analysis (n=117), imeglimin add-on to DPP-4 inhibitors reduced HbA1c by 1.02% versus placebo at 24 weeks, with consistent efficacy in both <65 and ≥65 years subgroups and a favorable safety profile (only one mild hypoglycemia).
Impact: Provides controlled evidence for imeglimin as an effective add-on to DPP-4 inhibitors, including in older adults, informing real-world optimization of combination therapy in T2D.
Clinical Implications: Consider imeglimin add-on in patients on DPP-4 inhibitors with inadequate control, especially when weight neutrality and low hypoglycemia risk are desired; monitor HbA1c response over 24 weeks.
Key Findings
- HbA1c decreased by −0.65% with imeglimin vs +0.38% with placebo at 24 weeks (difference −1.02%, p<0.001).
- Efficacy was consistent in <65 years (difference −0.79%, p=0.003) and ≥65 years (difference −1.22%, p<0.001).
- Safety was favorable with only one mild hypoglycemia event in the imeglimin group.
Methodological Strengths
- Randomized, double-blind, placebo-controlled design with trial registration.
- Predefined primary endpoint (HbA1c change) with subgroup analyses by age.
Limitations
- Interim analysis with modest sample size and 24-week duration.
- Japanese population limits generalizability pending broader multiethnic data.
Future Directions: Complete the 80-week open-label phase, assess durability and cardiometabolic outcomes, and evaluate imeglimin in diverse populations and in combination with GLP-1RA/SGLT2i.
AIMS: The ongoing FAMILIAR trial aims to provide evidence for clinical decision-making and offer a novel treatment paradigm in type 2 diabetes mellitus (T2DM) management. The interim findings of FAMILIAR through Week 24 are reported. MATERIALS AND METHODS: FAMILIAR is a multicentre, randomised, double-blind study comparing the efficacy and safety of imeglimin versus placebo in adult Japanese patients with T2DM and inadequate glycaemic control despite dipeptidyl peptidase-4 (DPP-4) inhibitor monotherapy, plus diet/exercise modifications. Patients entered a 24-week double-blind treatment phase (oral imeglimin 1000 mg or placebo twice daily) followed by an 80-week open-label phase (oral imeglimin 1000 mg twice daily). The primary end-point was change in glycated haemoglobin (HbA1c) level from baseline at Week 24. Safety was also monitored. RESULTS: Overall, 117 patients were randomised (imeglimin, n = 58; placebo, n = 54; excluded, n = 5). The least squares mean (standard error) changes in HbA1c level (baseline to Week 24) for the imeglimin and placebo groups, respectively, were -0.65% (0.11%) and 0.38% (0.11%) in the overall population (group-difference -1.02% [95% confidence interval -1.33%, -0.72%]; p < 0.001); -0.47% (0.17%) and 0.32% (0.18%) in patients aged <65 years (-0.79% [-1.29%, -0.29%]; p = 0.003); and -0.80% (0.14%) and 0.42% (0.14%) in patients aged ≥65 years (-1.22% [-1.61%, -0.82%]; p < 0.001). One patient in the imeglimin group had mild hypoglycaemia; the safety profile was favourable. CONCLUSIONS: Imeglimin represents a potential new treatment option for patients with T2DM and inadequate glycaemic control with DPP-4 inhibitors, including those aged ≥65 years. CLINICAL TRIAL REGISTRATION: jRCTs061210082.