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There is increasing evidence that translation is not limited to annotated protein-coding genes. Ribosome profiling sequencing, mass spectrometry-based proteomics, and immunopeptidomics have identified the productive translation of non-canonical open reading frames (ORFs). This suggests that the functional proteome includes not only conserved proteins but also proteins hidden in non-coding RNAs and de novo proteins. Some of these translated products are functional peptides, while others may be non-functional, potentially arising from evolutionary events. Several non-canonical ORF-encoded peptides have been found to regulate multiple physiological and pathological functions, particularly in cancer, immunity, and inflammation, indicating that they have potential as biomarkers and novel therapeutic targets. To better understand the diversity of functional peptides and translated non-canonical ORFs based on existing data, we summarize their classification according to transcriptional features and supporting evidence, including non-canonical ORFs located in ncRNAs and canonical mRNAs. This review provides a concise summary of the origin, discovery methods, and classification of non-canonical ORFs. It offers insights into the origins and functions of non-canonical ORF-encoded peptides from an evolutionary perspective, while also exploring the biological functions and regulatory mechanisms of these non-canonical ORF-encoded hidden proteins in tumorigenesis and progression.

Clinical efficacy with chimeric antigen receptor (CAR) T cells is currently limited by numerous factors including poor initial product phenotypes and lack of engagement of endogenous immunity. Vasoactive intestinal peptide (VIP) is an immunosuppressive neuropeptide, and the antagonism of its receptor (VIPR) on T cells potentiates T cell activation. We demonstrated that VIP suppresses CAR T cell function and engineered CAR T cells to secrete a short peptide drug that antagonizes VIPR (CAR/VIPRa). Armored CAR/VIPRa T cells maintained a memory phenotype and were metabolically quiescent after manufacturing yet mounted a strong bioenergetic response after antigen stimulation. Moreover, CAR/VIPRa T cells potentiated endogenous antitumor immunity through the recruitment of host T cells. In syngeneic and xenogeneic mouse models of hematological and solid tumors, CAR/VIPRa T cells exhibited greater tumor infiltration and maintained a less exhausted memory phenotype, resulting in superior antitumor efficacy. Together, these data show that VIPRa peptides produced by armored CAR T cells can enhance T cell function and boost endogenous immunity, thereby improving tumor control.

Polypharmacology is dedicated to the development of compounds acting on at least two targets (multi-target-directed ligands, MTDLs). In 2025, the European Medicines Agency (EMA) approved 38 drugs, and 11 out of them were MTDLs. Most of them are antibody-drug conjugates, bispecific antibodies, or kinase inhibitors, all of which are indicated for tumor treatment, including datopotamab deruxtecan (hormone receptor-positive, HER2-negative breast cancer), tisotumab vedotin (advanced cervical carcinoma), linvoseltamab (fourth-line treatment of multiple myeloma), and erdafitinib (advanced urothelial carcinoma). The small molecule tiratricol is an orphan drug, which is indicated for the treatment of the very rare Allan-Herndon-Dudley syndrome. The second part of the present review is dedicated to the post-marketing safety surveillance of MTDLs approved by the EMA in 2022-2024. For 19 out of the 27 MTDLs, which are still available on the European market, comprehensive pharmacovigilance studies, mainly based on the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS), were found. New safety signals have been identified, including Stevens-Johnson syndrome and progressive multifocal leukoencephalopathy. The analysis also revealed a more favorable safety profile of the MTDL tirzepatide (a dual glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide analogue) compared to the single-targeted drug semaglutide (glucagon-like peptide-1 analogue), including lower reporting rates of acute kidney injury and no significant suicidality signal. Not applicable.

Bremelanotide (BRM) is a cyclic peptide therapeutic whose intrinsic stability and degradation behavior have not been extensively investigated. This study aimed to develop a stability-indicating RP-HPLC method for BRM and characterize its degradation products using LC-HRMS/MS combined with computational approaches. Stress degradation studies were conducted according to International Council for Harmonization guidelines under acidic, basic, neutral hydrolytic, oxidative, thermal, and photolytic conditions. The RP-HPLC method was developed using a YMC Pack C8 column with 10 mM ammonium formate buffer (pH 3.0) and acetonitrile containing 0.1% formic acid as the mobile phase in gradient mode. The method was partially validated and showed satisfactory system suitability, precision, and accuracy. Excellent linearity was achieved over 25-150 µg mL-1 with a coefficient of determination (r2) of 0.9993. Forced degradation studies revealed that BRM exhibited lower degradation under acidic conditions compared with basic conditions and showed significant susceptibility to oxidative conditions. Furthermore, degradation was also observed under thermal and photolytic stress conditions. A total of eight degradation products were detected and characterized by LC-HRMS/MS. The major degradation pathways involved deacetylation, peptide-bond hydrolysis, oxidation, and epimerization. Epimerized products were identified, and probable stereochemical sites were predicted using energy minimization by correlating steric energies with MS/MS fragment relative intensities. ProTox-3.0-based in silico toxicity prediction indicated that most degradation products belonged to toxicity class 5, while two hydrolytic products were classified as class 4. Overall, this study provides valuable insights into BRM stability behavior and supports peptide API/formulation development, impurity profiling, and quality control.

Macrocyclic peptides are emerging as a powerful therapeutic modality owing to their potential oral bioavailability and capacity to engage targets long considered undruggable. The introduction of aromatic heterocycles into macrocycles further expands this structural space by imparting distinct conformational preferences. However, accurate determination of the solution-state structures and dynamics of the resulting molecules remains challenging. Here, we integrate complementary isotropic and anisotropic NMR observables with enhanced sampling simulations and density functional theory (DFT) calculations to systematically investigate aryl- and heterobiaryl-containing cyclic peptides in different solvent systems. Our results based on residual dipolar coupling (RDC) measurements reveal conformational dynamics of macrocycles and significantly extend the knowledge gained by conventional NMR analysis based on nuclear Overhauser effects (NOEs) by more faithfully capturing the solution-state ensembles. Our methodology enables conformational analysis in both fast- and slow-exchange regimes on the NMR time scale. Notably, up to three interconverting backbone conformers at the DFT level are required to fully reconcile the experimental data for each ring system. We identify aryl and heterobiaryl motifs as structural elements governing the conformational landscape in our systems, modulating the populations of multiple thermodynamically accessible states characterized by distinct intramolecular hydrogen-bonding networks and unusual backbone geometries. Together, this integrative NMR-computational framework provides a precise and general strategy for resolving complex conformational ensembles of macrocycles, which should inform the objectives for synthetic modification and pave a way for the structure-based rational design of next-generation peptide therapeutics.

Heart failure with preserved ejection fraction (HFpEF) accounts for a growing proportion of heart failure cases. Pulmonary congestion, particularly subclinical congestion, is often underestimated by symptoms and physical examination. Lung ultrasound enables detection of extravascular lung water through B-lines, even in early stages, but its role in HFpEF patients managed in primary care remains poorly defined. This prospective, multisite observational study included ambulatory HFpEF patients with a prior hospitalization for heart failure decompensation and stable New York Heart Association class over the previous 3 months. Baseline evaluation included clinical assessment, biomarkers (N-terminal pro-brain natriuretic peptide, cancer antigen 125), frailty index, HF-related quality of life, 6-minute walking test, and bed-side lung ultrasound using a 28-zone protocol. Patients with pleural effusions were excluded, and B-lines were quantified offline. A total of 188 patients were analyzed (age 77.3 ± 9.9 years, 52.1% women, 46.9% obese, 81.9% New York Heart Association II, N-terminal pro-brain natriuretic peptide 974 pg/mL, 76% loop diuretic). Overall, 86.5% of patients showed at least one B-line, and one-third had ≥5 B-lines despite clinical stability. Higher B-line count was associated with higher systolic blood pressure, pulmonary crackles, and increased N-terminal pro-brain natriuretic peptide and cancer antigen 125 levels. In contrast, no significant relationship was found between B-lines and 6-minute walking test, frailty index, or HF-related quality of life. In stable ambulatory HFpEF patients managed in primary care, lung ultrasound frequently identifies subclinical pulmonary congestion. B-lines are associated with biomarkers of congestion, crackles, and systolic blood pressure, but not with functional capacity, frailty, or patient-reported health status.

Evidence supporting the use of sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1-RA) in individuals aged ≥ 80 years remains limited, particularly regarding treatment persistence and real-world outcomes. In this retrospective real-world study, 292 individuals with type 2 diabetes (T2D) aged ≥ 80 years who started SGLT2i (n = 155) or GLP1-RA (n = 137) after the age of 75 were stratified by age at treatment initiation (75-80 vs. > 80). Primary outcomes were all-cause mortality and treatment persistence; longitudinal renal function was also assessed. Survival analyses were performed using Cox models adjusted for confounders. Over a median follow-up of 40 (37-43) months, 47 deaths (16.1%) occurred. The incidence rate of mortality was 37.5 and 68.6 events/1000 person-years in the GLP1-RA and SGLT2i groups, respectively (adjusted HR = 0.58, 95% CI [0.28-1.21]; p = 0.148). Stratifying participants by age at first prescription, those starting either GLP1-RA or SGLT2i at age 75-80 showed similar mortality. In contrast, subjects starting GLP1-RA vs. SGLT2i after 80 years showed a higher survival rate (adjusted HR = 0.33, 95% CI [0.12-0.91]; p = 0.034); significance disappeared after further adjustment for cardiovascular burden. Treatment discontinuation was 14% with GLP1-RA and 20% with SGLT2i (HR 0.53, 95% CI [0.30-0.95]; p = 0.032), due to a better persistence in GLP1-RA of more elderly subjects. Longitudinal eGFR trajectories were similar between treatments. GLP1-RA and SGLT2i were associated with similar all-cause mortality risk when started in very late age. Kidney function over time was comparable. Persistence on SGLT2i was lower when therapy was started after the age of 80. These findings highlight the need for individualized treatment decisions in older, frail patients and for prospective studies on glucose-lowering therapies in very old populations.

Interleukin-11 (IL-11), a member of the IL-6 cytokine family, is well-recognized for its role in driving fibrosis and stromal remodeling. Extensive research on this fibroblast-associated cytokine have focused on its roles in tissue scarring and extracellular matrix deposition. However, emerging evidence has unveiled its sophisticated role in immunomodulation, extending far beyond its conventional pro-fibrotic functions. This review demonstrates how IL-11 influences phenotypic shifts of immune cell plasticity within both innate and adaptive compartments. In the myeloid lineage, IL-11 orchestrates macrophage polarization and macrophage-to-mesenchymal transition (MMT), regulates neutrophil extracellular traps (NETs) formation, and modulates the plasticity of NK cells, while in the lymphoid compartment, it influences T helper cell differentiation, regulatory T cell stability, and B cell responses. Of note, the effect of IL-11 on immune cells may be exerted either directly through engagement with the target cells or indirectly via intercellular crosstalk. Furthermore, we also highlight the therapeutic potential of modulating the IL-11 signaling axis through monoclonal antibodies, siRNAs, peptides, recombinant proteins, and small molecules to restore immune homeostasis across multiple disease states.

Gastroparesis is a condition of delayed gastric emptying in the absence of gastric outlet obstruction. Based on a 2018 US administrative health insurance claims database study, prevalence of definite gastroparesis (with documented delayed gastric emptying) was 21.5 per 100 000 persons. Gastroparesis, which is caused by reduced contractions of the distal stomach or abnormal pyloric relaxation, is more common among females than males (ratio, 2:1-4:1) and typically causes nausea, vomiting, early satiety, bloating, and abdominal pain or discomfort. In a large US epidemiological study involving 82.6 million patients, the most common causes of gastroparesis were type 2 diabetes (51.7%), postsurgical effects (15%), medication-induced (11.8%), idiopathic (11.3%), type 1 diabetes (5.7%), and other (4.5%). Other risk factors include neurological disorders (eg, Parkinson disease), hypothyroidism, amyloidosis, connective tissue disorders (eg, scleroderma), and viral infections (eg, norovirus, cytomegalovirus, Epstein-Barr virus, SARS-CoV-2). The 2022 American College of Gastroenterology and the 2025 American Gastroenterological Association (AGA) guidelines define the criterion standard diagnostic test for gastroparesis as gastric emptying scintigraphy with more than 10% gastric retention at 4 hours in patients with symptoms of gastroparesis without mechanical obstruction based on upper endoscopy or abdominal imaging such as computed tomographic (CT) scan. The carbon 13 spirulina stable isotope breath test is also approved for diagnosing gastroparesis by the US Food and Drug Administration. Based on the percentage of gastric retention at 4 hours, gastroparesis is categorized in the 2022 AGA clinical practice update as mild (10%-15%), moderate (16%-35%), or severe (>35%). Treatment includes discontinuation of medications that delay gastric emptying such as opioids, cannabis, anticholinergics, and glucagon-like peptide-1 receptor agonists and for patients with diabetes, optimizing glycemic control. First-line therapies according to the AGA 2022 clinical practice update are a small particle diet (food that is blended or chopped into small pieces) that is low in fat and nondigestible fiber and antiemetics (eg, serotonin 5-hydroxytryptamine 3 [5-HT3] receptor antagonists, histamine H1 receptor antagonists) for mild gastroparesis; antiemetics and prokinetics (metoclopramide, erythromycin) for moderate gastroparesis, and liquid diet or jejunal enteral feeding for severe gastroparesis. Severe refractory gastroparesis may be treated with gastric peroral endoscopic myotomy (G-POEM), which involves endoscopic-guided incision of the pylorus sphincter muscle, or gastric electrical simulation, in which an implanted neurostimulator sends electrical pulses to the stomach muscle. Gastroparesis is a condition of delayed gastric emptying without gastric outlet obstruction that is diagnosed based on a gastric emptying study. First-line treatments include a small particle diet and antiemetics and prokinetics. Severe refractory gastroparesis may be treated with procedures such as G-POEM or gastric electrical simulation.

T cell fate is partly determined by T cell receptor (TCR) affinity for its cognate peptide ligand. During thymic selection, CD4+ T cells with higher affinity for self-antigens are more likely to be deleted or become FOXP3+ natural T regulatory (nTreg) cells. However, downstream transmembrane adaptor proteins such as the T cell receptor associated transmembrane adaptor 1 (TRAT1) also modulate T cell activation. Here we show that TRAT1 decreases the activation threshold of human naïve CD4+ T cells and mediates TCR activation leading to transient FOXP3 expression via FOXO3A. Individuals at high risk for autoimmune type 1 diabetes (T1D) had increased proportions of CD4+ T cells with elevated TRAT1 expression in their naïve CD4+ T cell compartment. Naïve CD4+ T cells transduced with an insulin-specific TCR-TRAT1 construct exhibited enhanced proliferation, even in the absence of exogenously added insulin peptide, and showed heightened sensitivity to low doses of insulin peptide. These findings reveal an additional layer of T cell reactivity regulation independent of TCR affinity, which may underlie homeostatic and pathogenic functions of human T cells.

To assess the efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in kidney transplant recipients (KTRs) with post-transplant diabetes mellitus (PTDM). This retrospective, single-center cohort study included 24 KTRs with PTDM who initiated GLP-1 RA therapy as an add-on to existing treatments between August 2013 and April 2024. Outcomes assessed included fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), body weight, body mass index (BMI), blood pressure, lipid profile, renal function, and adverse events, with data collected at baseline and last follow-up. Over a mean follow-up of 3.2 &#xb1; 2.1 years, GLP-1 RA therapy was associated with trends toward weight loss (-3.6 &#xb1; 8.5 kg; p = 0.051) and BMI reduction (-1.4 &#xb1; 3.3 kg/m2; p = 0.056). HbA1c decreased by -0.2% (p = 0.362), while FPG increased by +12.1 mg/dL (p = 0.232). Significant improvements were observed in total cholesterol (-41.5 mg/dL; p < 0.001) and systolic blood pressure (-8.5 mmHg; p = 0.041). Serum creatinine and estimated glomerular filtration rate remained stable (-0.09 mg/dL, p = 0.305; +3.2 mL/min/1.73 m2, p = 0.206, respectively). Nausea occurred in 21% (n = 5), and no other severe adverse events were reported. In KTRs with PTDM, GLP-1 RA therapy was associated with improvements in lipid profile and blood pressure, accompanied by non-significant trends toward weight reduction and stable renal function, and demonstrated an acceptable safety profile. Prospective studies are warranted to confirm long-term cardiorenal benefits.

The six complementarity determining regions (CDRs) of the T cell receptor (TCR) form multiple contacts with cognate peptide and major histocompatibility complex, thus determining antigen specificity. However, the contacts between the CDRs themselves are less understood. Our systematic study of all available TCR crystallographic structures identified consistent patterns of intra- and inter-chain CDR contacts in both free and antigen-bound TCRs. In addition, the protein sequences of TCR&#x3b1; and TCR&#x3b2; from sets of TCRs which recognise a shared antigen shared mutual information and were not independent. As a result, sequence-based models can partially predict TCR&#x3b1;/TCR&#x3b2; pairing de novo. The conserved patterns of CDR amino acid contacts, and the mutual sequence constraints between antigen-specific sets of TCR &#x3b1; and &#x3b2; chains represent an under-appreciated element of TCR structure, which may play an important role in T cell antigen recognition. The code and data necessary to reproduce the analyses are available at https://github.com/mm523/TCRab-pairing. Supplementary data are available at Bioinformatics online.

Competition between organisms is a ubiquitous feature of life on Earth and a major driver of evolutionary innovation. As Earth's most diverse and abundant organisms, bacteria employ numerous strategies to inhibit the growth of competitors, ranging from the production of diffusible antibiotic metabolites to the secretion of sophisticated protein toxins. Although secreted antibacterial protein toxins have been extensively studied in gram-negative bacteria, analogous systems employed by gram-positive organisms remain comparatively poorly understood. Recent work has shed light on a widespread family of secreted protein toxins associated with co-secreted serine proteases that likely mediate interbacterial competition among gram-positive species. These systems, termed antibacterial protein (ABP) systems, consist of a secreted polymorphic toxin (AbpT), a co-secreted serine protease (AbpP), and a cytoplasmic immunity protein (AbpI). Following proteolytic processing, ABP toxins inhibit the growth of a remarkably diverse range of gram-positive bacteria spanning the phyla Bacillota and Actinomycetota. Existing evidence suggests that these proteins combine the properties of cationic antimicrobial peptides with those of classical polymorphic antibacterial toxins, potentially enabling toxin delivery into distantly related bacteria. In this review, we summarize the current understanding of the organization, mechanisms, and ecology of ABP systems; discuss major outstanding questions regarding toxin import and native biological function; and highlight opportunities for future mechanistic and biotechnological investigation in this emerging field.

Excessive body weight stands out as a major, well-documented risk factor for rheumatic and musculoskeletal diseases (RMDs). Indeed, high body mass index (BMI) affects disease severity, treatment response, and long-term outcomes. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) were first developed for type 2 diabetes and obesity, but there is growing evidence that they may also have anti-inflammatory and immunomodulatory properties [1-3]. This narrative review examines the available evidence on the role of GLP-1 RAs in two conditions that are strongly associated with metabolic and mechanical factors but sit on almost opposite ends of the inflammatory spectrum: osteoarthritis (OA), a predominantly mechanically driven disease, and psoriatic disease (PsD), an immune-mediated inflammatory disease. A comprehensive narrative review of the literature was conducted to evaluate preclinical and clinical evidence regarding the effects of GLP-1 signaling in both OA and PsD. Preclinical data suggest that GLP-1 signaling may protect cartilage, reduce inflammation, and alleviate pain in OA. Early clinical evidence is encouraging, showing reductions in both joint pain and body weight. In PsD, obesity and psoriatic inflammation share several common pathways, particularly through the IL-17/IL-23 axis, which provides a theoretical biological rationale for GLP-1 RAs use in this setting, although direct clinical evidence remains limited and largely derived from studies in obese patients. Dedicated randomized controlled trials are necessary to clarify the direct immunomodulatory mechanisms involved and to define the precise position of GLP-1 RAs in rheumatological practice.