Peptide Research Database

International expert panel review for the use of resmetirom and semaglutide in the management of MASH-related fibrosis: clinical practice update.

In a research review, the proposed framework is intended to evolve as long-term outcomes data emerge and additional MASH therapies become available.

Mironova M, Ratziu V, Rinella ME, Bansal MB, Noureddin M, Alkhouri N, Anstee QM, Newsome PN, Schattenberg JM, Sanyal AJ, Loomba R

The recent conditional US Food and Drug Administration (FDA) approval of two therapies, resmetirom (Rezdiffra) and semaglutide (Wegovy), marks the first time clinicians have pharmacological therapy for metabolic dysfunction-associated steatohepatitis (MASH) with significant fibrosis (F2-F3) without cirrhosis, a disease that previously had no available pharmacological treatment. The two agents act through complementary mechanisms: resmetirom as a liver-directed thyroid hormone receptor-beta agonist and semaglutide as a glucagon-like peptide-1 receptor agonist (GLP-1 RA) with a broad spectrum of metabolic effects. In this international expert panel review, we consolidate data from phase III trials, FDA labels and emerging clinical experience into a single resource. It covers the entire care pathway: non-invasive test-based diagnosis of MASH with significant fibrosis, treatment selection and initiation, on-treatment monitoring and response assessment. We offer practical recommendations for individualising therapy by patient phenotype, managing patients already receiving GLP-1 RAs and defining response, non-response and criteria for switching or combining agents. The proposed framework is intended to evolve as long-term outcomes data emerge and additional MASH therapies become available.

Maternal Kisspeptin-10 Treatment Partially Rescues Fetal and Postnatal Cardiac Programming Disrupted by Maternal Hypothyroidism.

In a rat study, collectively, these findings demonstrate that maternal hypothyroidism disrupts cardiac development and postnatal cardiac programming, whereas maternal Kp10 administration partially mitigates these effects, highlighting new mechanisms through which kisspeptin may positively regulate cardiac development.

Barbosa EM, Rodrigues NP, Santos BR, Dos Anjos Cordeiro JM, da Silva TQM, Oliveira CL, Santos LC, Cunha MCDSG, Serakides R, Silva JF

Cardiovascular diseases are the leading cause of global mortality and have been associated with alterations in fetal programming. Maternal hypothyroidism (MH) impairs placental function and induces intrauterine growth restriction (IUGR), both of which are risk factors for cardiovascular disease. Kisspeptin-10 (Kp10) has been shown to improve feto-placental development in hypothyroid rats, but its effects on intrauterine cardiac development remain unknown. MH was induced in Wistar rats using propylthiouracil (PTU), and Kp10 administration began on gestational day 8. Offspring hearts were analyzed at fetal day 18 and postnatal days 3 and 21. MH reduced fetal and postnatal body and heart mass, impaired cardiomyocyte proliferation, and dysregulated apoptotic and angiogenic markers. Maternal Kp10 administration enhanced postnatal weight gain, restored cardiomyocyte proliferation and nuclear density, and positively modulated apoptotic (Bax/Bcl2) and angiogenic (Vegf, Ang2, Flk1) pathways. However, it increased redox (8-OHdG) and endoplasmic reticulum (ER) stress (Grp78, Chop) mediators in fetal hearts, while reduced postnatal Chop expression in both sexes. Collectively, these findings demonstrate that maternal hypothyroidism disrupts cardiac development and postnatal cardiac programming, whereas maternal Kp10 administration partially mitigates these effects, highlighting novel mechanisms through which kisspeptin may positively regulate cardiac development.

Postoperative outcomes after total knee arthroplasty in type 2 diabetes mellitus patients receiving semaglutide versus tirzepatide: a propensity score-matched national research network analysis.

In a clinical study, these findings support continued perioperative use of either agent in T2DM patients undergoing TKA.

Wu KA, Choudhury A, Wu JA, Shenoy DA, Song J, Mai E, Dhanjani S, Shatkin M, Wellman SS, Seyler TM, Moucha CS, Hayden BL

Semaglutide (GLP-1 receptor agonist) and tirzepatide (dual GIP/GLP-1 agonist) are increasingly prescribed to adults with type 2 diabetes mellitus (T2DM) undergoing total knee arthroplasty (TKA). Whether short-term postoperative outcomes differ between these agents was unknown. This was a retrospective cohort study using the TriNetX research network database. Adults with T2DM who underwent primary TKA between June 1, 2022, and December 31, 2024, and had an active prescription for semaglutide or tirzepatide within 90 days preoperatively were eligible. 1:1 propensity score matching was conducted on age, sex, race, body mass index, hemoglobin A1c, comorbidity burden, and concurrent diabetes medication use, yielding 415 matched pairs. Outcomes through 90 and 180 days included medical complications, surgical complications, and healthcare utilization. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated using logistic regression. After matching (n = 830), there were no differences in 90-day medical complications (OR 1.122, 95% CI 0.736-1.710; P = 0.591) or 180-day surgical complications (OR 1.632, 95% CI 0.845-3.152; P = 0.141) between semaglutide and tirzepatide cohorts. Individual events, including myocardial infarction, stroke, pneumonia, sepsis, pulmonary embolism, deep vein thrombosis, acute kidney injury (OR 0.867, 95% CI 0.417-1.801; P = 0.701), urinary tract infection (OR 1.562, 95% CI 0.863-2.827; P = 0.138), surgical site infection (OR 1.726, 95% CI 0.782-3.810; P = 0.172), periprosthetic joint infection, wound dehiscence, mortality, and revision-were statistically similar (all P > 0.05). Emergency department visits and/or readmissions were comparable at 90 days (OR 0.775, 95% CI 0.570-1.052; P = 0.102) and 180 days (OR 0.887, 95% CI 0.672-1.170; P = 0.397). Several outcomes had low event counts in both groups, limiting precision. In a large, propensity-matched national cohort of primary TKA, semaglutide and tirzepatide demonstrated similar short-term safety and utilization profiles. These findings support continued perioperative use of either agent in T2DM patients undergoing TKA.

Crusted Scabies as a Complication of Severe Endogenous Hypercortisolism Due to Occult Ectopic ACTH Syndrome: A Case Report

In a case report, this case highlights crusted scabies as a rare infectious complication of severe naturally occurring hypercortisolism and emphasizes the importance of early recognition of atypical parasitic infections in immunocompromised patients.

Yücel¹ HD, Çakır¹ SD, Aktaş² E, Kızılçay¹ ZA, Şahin¹ K, Tunç¹ ÜA, Adaş¹ M.

Abstract Crusted scabies is a severe, highly contagious variant of scabies that occurs predominantly in immunocompromised individuals. Severe endogenous hypercortisolism caused by ectopic adrenocorticotropic hormone (ACTH) syndrome results in profound immune dysfunction and increases susceptibility to opportunistic infections. However, crusted scabies associated with occult ectopic ACTH syndrome has not previously been reported. A 52-year-old man presented with progressive weight gain, peripheral edema, and cushingoid features. Biochemical and dynamic endocrine testing confirmed ACTH-dependent hypercortisolism, while pituitary evaluation and extensive imaging failed to identify the ACTH source, leading to the diagnosis of occult ectopic ACTH syndrome. During hospitalization, hyperkeratotic lesions on the hands and feet were diagnosed as biopsy-confirmed crusted scabies. The patient was treated with oral ivermectin and topical permethrin, while hypercortisolism was managed with staged bilateral adrenalectomy and metyrapone therapy. Cutaneous lesions regressed following antiparasitic treatment, accompanied by progressive metabolic improvement. This case highlights crusted scabies as a rare infectious complication of severe endogenous hypercortisolism and emphasizes the importance of early recognition of atypical parasitic infections in immunocompromised patients.

Glycine Transporter 1 Inhibitor, Bitopertin, Changes Excitatory and Inhibitory Network Connectivity in Mouse Medial Prefrontal Cortex.

In a mouse study, together, we found that bitopertin chiefly impacts the inhibitory network, while minimally affecting PNs.

Graf M, Ponserre M, Sadeh S, Robinson J, Coy M, Hunger M, Lien A, Ursu D, Omrani A, Magno L, Hengerer B, Rosenbrock H, Augustine GJ, Chen-Engerer HJ

Cognitive deficits in Schizophrenia (SCZ) are correlated with excitation-inhibition (E/I) imbalance within the medial prefrontal cortex (mPFC). E/I imbalance may arise from N-methyl-D-aspartate receptor (NMDAR) hypofunction and dysfunction of GABAergic neurotransmission. Previous research has shown that bitopertin, a glycine transporter 1 (GlyT1) inhibitor, restores E/I balance. We investigated how GlyT1 inhibition affects NMDAR-mediated signaling and reshapes connectivity between excitatory and inhibitory neurons in the mPFC. We examined the effect of bitopertin on NMDAR-mediated transmission between pyramidal neurons (PNs) and inhibitory interneurons (INs), including putative vasoactive intestinal peptide-expressing (VIP-like), putative somatostatin-expressing (SST-like), and parvalbumin-expressing (PV) INs in the mouse mPFC. Our study utilized several complimentary techniques including channelrhodopsin-assisted circuit mapping, two-photon ex vivo functional imaging, slice electrophysiological recordings, and network modeling. Bitopertin influenced NMDAR-mediated excitatory drive in an IN-subtype-specific manner, with a presynaptic independent mechanism. It had no effect on the EPSC input strength of VIP-like INs but decreased the input probability and area from which VIP-like INs received excitation. By contrast, Bitopertin strengthened excitatory synaptic connections to PV INs but had no effect on excitatory input area or probability. While increased excitation of inhibitory INs was expected to inhibit PN activity, the results showed no significant inhibition of PNs. This work uncovers the mode of action of bitopertin and the effects of GlyT1 inhibition on NMDA transmission within the mPFC network. Computational modeling suggests that these changes could contribute to partial normalization of network dynamics under simulated conditions of E/I imbalance mediated by NMDAR hypofunction. Together, we found that bitopertin chiefly impacts the inhibitory network, while minimally affecting PNs. This insight could aid the development of more effective therapies for cognitive dysfunctions caused by E/I imbalance.

Weight loss with a lower dose compounded semaglutide and behavioral weight management program: A real-world matched retrospective cohort study

This study found at 16 weeks, NW users lost 2.6%, NMGP users lost 8.3%, and NGP users lost 9.1% of their initial weight (all comparisons p Conclusions This large, looking back at past data cohort reports lower doses of compounded semaglutide alongside a behavioral companion achieve 91% of the weight loss of a higher dose of compounded semaglutide in the first 16 weeks.

Owen EC, Moulder RG, Morse JL, Ainsworth MC, Fabry A, Merner AR.

Objective This 16-week, real-world retrospective cohort study of a behavioral weight management program evaluated the efficacy of a lower dose of compounded semaglutide on weight loss. Methods Weight loss was compared among Noom Weight (NW) users, Noom Microdose GLP-1 Rx Program (NMGP) users prescribed a low dose of compounded semaglutide (up to 0.6mg/weekly), and Noom GLP-1 Rx Program (NGP) users prescribed a dose up to 1.2mg/weekly of compounded semaglutide via multiple-group latent growth curve models for the full sample and propensity score matched cohort. Users were matched on demographic characteristics, Area Deprivation Index, baseline Body Mass Index, and urbanicity. Results In the full sample, participants (N = 29,788) were mostly middle-aged, urban-dwelling females. At 16 weeks, NW users lost 2.6%, NMGP users lost 8.3%, and NGP users lost 8.6% of their baseline weight (all comparisons p ≤ .001). In the matched cohort (N = 3,657; n= 1,219 per group), participant characteristics were similar. At 16 weeks, NW users lost 2.6%, NMGP users lost 8.3%, and NGP users lost 9.1% of their initial weight (all comparisons p Conclusions This large, retrospective cohort reports lower doses of compounded semaglutide alongside a behavioral companion achieve 91% of the weight loss of a higher dose of compounded semaglutide in the first 16 weeks.

Tubacin induces TFEB-dependent ferritinophagy independently of HDAC6 and sensitizes cancer cells to ferroptosis under GSH-GPX4 axis disruption.

This study found collectively, our findings identify TFEB-driven lysosomal activation and ferritinophagy as a critical determinant of ferroptotic sensitivity under redox imbalance and suggest that pharmacological modulation of TFEB-lysosomal function by tubacin may represent a potential strategy for enhancing ferroptosis-based cancer therapy.

Kim G, Jang SK, Kim DG, Kim H, Lee JH, Bae S, Park IC, Jin HO

Histone deacetylase 6 (HDAC6) is a promising therapeutic target in cancer. However, its inhibitors show limited efficacy as monotherapies and are more effective in combination settings, suggesting a context-dependent mechanism that remains poorly defined. Here, we show that tubacin sensitizes cancer cells to ferroptosis under glutathione (GSH) depletion caused by buthionine sulfoximine (BSO). This effect was not observed with other HDAC6 inhibitors or with HDAC6 depletion, suggesting a mechanism not solely attributable to HDAC6 inhibition. Co-treatment with tubacin and BSO induced lipid peroxidation, which was abrogated by ferroptosis inhibitors, indicating ferroptosis as the predominant mode of cell death. Mechanistically, tubacin activated transcription factor EB (TFEB), leading to lysosomal acidification and expansion, accompanied by ferritin degradation and increased intracellular ferrous iron. These effects were reversed by TFEB silencing, lysosomal inhibition, or nuclear receptor coactivator 4 depletion, supporting a role for TFEB-dependent lysosomal ferritinophagy. However, iron accumulation driven by tubacin was insufficient to trigger ferroptosis, indicating a requirement for redox imbalance. Consistently, tubacin enhanced ferroptosis under GSH-glutathione peroxidase 4 (GPX4) axis disruption by imidazole ketone erastin or arsenic trioxide. Collectively, our findings identify TFEB-driven lysosomal activation and ferritinophagy as a critical determinant of ferroptotic sensitivity under redox imbalance and suggest that pharmacological modulation of TFEB-lysosomal function by tubacin may represent a potential strategy for enhancing ferroptosis-based cancer therapy.

Reduced Risk in Melanoma and Nonmelanoma Skin Cancers in Obese Patients on Semaglutide and Tirzepatide.

Alameddine R, Roecker A, Jabin M, Wagner RF

Tirzepatide and oral progestogens: A hypothesis-generating review of a biologically plausible pharmacokinetic interaction in gynaecologic disease control and menopausal hormone therapy.

In a research review, whether tirzepatide meaningfully alters the clinical effectiveness of oral progestogens is untested; the possibility is biologically plausible but unproven, and dedicated how the body processes the drug and prospective clinical studies are required.

Viana DPDC, Invitti AL, Jacobsen L, Schor E

Tirzepatide, a dual incretin receptor agonist, is increasingly prescribed to women in midlife, many of whom also use oral progestogens for gynaecologic disease control or for endometrial protection during menopausal hormone therapy. Because tirzepatide delays gastric emptying, it may alter the absorption of co-administered oral drugs. This hypothesis-generating narrative review, based on a structured search of PubMed/MEDLINE, EMBASE and the Cochrane Library through February 2026, examines the biological plausibility of such an interaction and the limits of the current evidence. In the only available pharmacokinetic study, a single 5 mg dose of tirzepatide given with a combined oral contraceptive reduced the peak plasma concentration of ethinylestradiol, norgestimate and its active metabolite norelgestromin by 59%, 66% and 55%, and reduced overall exposure by 20%, 21% and 23% respectively, delaying time to peak by 2.5 to 4.5 h. The much smaller reduction in exposure to the active metabolite illustrates that a fall in peak concentration cannot be equated with reduced efficacy. No equivalent data exist for progestogens used in therapeutic gynaecologic or menopausal indications, and findings obtained with one contraceptive formulation cannot be extrapolated automatically to structurally different agents. The effect on gastric emptying is greatest after the first dose and diminishes with continued treatment, so any risk would be concentrated during initiation and dose escalation. Whether tirzepatide meaningfully alters the clinical effectiveness of oral progestogens is untested; the possibility is biologically plausible but unproven, and dedicated pharmacokinetic and prospective clinical studies are required.

Carbon Emission Impact of Semaglutide in People with Obesity in the UK Using a Disease Modelling Approach.

In a clinical study, scenario and sensitivity analyses confirmed the robustness of the results. Aimed to assess the carbon footprint and clinical outcomes of once-weekly semaglutide in people with overweight or obesity in the UK using a disease modelling approach.

Lund N, Lübker C, Rasche A, Taylor M, Xu W, Taneja L, Shukla S, Olivieri AV, Sharma Y

We aimed to assess the carbon footprint and clinical outcomes of once-weekly semaglutide in people with overweight or obesity in the UK using a disease modelling approach. A per-patient carbon footprint analysis was conducted to estimate emissions related to obesity management with semaglutide 2.4 mg as an add on to diet and exercise versus diet and exercise alone. A Markov state-transition cohort model (Core Obesity Model) was used for the analysis. Data were sourced from STEP and SELECT trials across three populations: (1) body mass index [BMI] ≥ 30 or ≥ 27 with one or more obesity-related complications (BMI30+/BMI27+C), (2) BMI ≥ 27 with one or more complications, including type 2 diabetes mellitus (BMI27+C), and (3) BMI ≥ 27 with established cardiovascular disease (BMI27+CVD). Carbon emissions were estimated using resource-based and cost-based methods. Key outcomes included life-years, quality-adjusted life-years, and incremental carbon footprint effectiveness ratio. In the BMI30+/BMI27+C and BMI27+C populations, semaglutide was dominant, yielding 0.30 and 0.25 additional life-years, 0.51 and 0.46 additional quality-adjusted life-years, while reducing lifetime carbon emissions by 1.8% (9850 vs 10,030 kg of CO2 equivalent [CO2e]) and 1.9% (9792 vs 9983 kg CO2e), respectively. Manufacturing emissions of semaglutide were offset by reductions in carbon emissions resulting from fewer obesity-related complications. In the BMI27+CVD population, semaglutide improved life-years by 0.56 and quality-adjusted life-years by 0.59, but emissions increased (14,700 vs 14,444 kg CO2e) because of longer survival and increased monitoring. Scenario and sensitivity analyses confirmed the robustness of the results. Semaglutide offers both clinical and environmental benefits in obesity management, supporting the UK's net-zero emissions goals.