Diabetes drives a major burden of kidney failure, cardiovascular disease, and premature mortality, yet current clinical markers incompletely capture individual trajectories of organ decline. Soluble tumor necrosis factor receptors 1 and 2 (sTNFR1/2) have emerged as among the most reproducible circulating predictors of diabetic kidney disease progression, retaining prognostic value after adjustment for estimated glomerular filtration rate (eGFR) and albuminuria across multiple cohorts. Prospective studies in type 2 diabetes also associate higher sTNFR1/2 with incident cardiovascular events and all-cause mortality, supporting a systemic risk phenotype that is not fully explained by baseline kidney measures. Mechanistically, recent work has refined the classical view of tumor necrosis factor (TNF) as a generic inflammatory mediator by identifying proximal checkpoints that govern TNFR1 “injury-biased” outputs, including ubiquitination- and lipidation-dependent control of RIPK1, trafficking-dependent restraint of death-receptor signaling, and cross-pathway phosphorylation that retunes downstream complex assembly. In parallel, advances in therapeutic engineering are shifting the field from non-selective TNF neutralization toward receptor-selective modulation, including TNFR1-selective antagonists, allosteric inhibitors, and shedding strategies designed to reduce injury signaling while preserving TNFR2-linked immunoregulatory and reparative programs. This receptor-resolved framework provides a coherent basis for interpreting why soluble receptors outperform circulating TNF as prognostic biomarkers and for developing mechanism-informed interventions in diabetes.

Diabetic Kidney Disease (DKD) is strongly related to ferroptosis, an iron-dependent form of programmed cell death characterized by the accumulation of lipid peroxides. While ferroptosis is a pivotal mediator in DKD pathogenesis, its upstream regulatory mechanism remains poorly defined, thus impeding the development of targeted therapeutic strategies. In this study, by integrating multi-omics clinical data (GSE96804 and GSE104954) and combining machine learning algorithms, the RNA-binding protein ZFP36 was screened out as the core regulatory factor of ferroptosis in DKD. The results revealed that the expression level of ZFP36 in the DKD group was significantly lower than that in the normal group. Functional experiments demonstrated that overexpression of ZFP36 could significantly alleviate lipid peroxidation, iron ion accumulation, and cellular fibrosis, thereby inhibiting ferroptosis and alleviating kidney damage. Transcriptome analysis further revealed that ZFP36 regulated key genes related to oxidative stress and iron metabolism. Additionally, molecular docking simulations revealed strong binding affinity between ZFP36 and bioactive natural products such as berberine and astragalus, providing a potential mechanism for its renal protective effect. Overall, ZFP36 was hereby established as an important inhibitor of ferroptosis in DKD, highlighting its potential as both a biomarker and a therapeutic target for its precision diagnosis and intervention.

Renal dysfunction is an important complication of primary hyperparathyroidism (pHPT). However, the factors associated with a decline in estimated glomerular filtration rate (eGFR) in patients with pHPT have not been fully investigated. This study aimed to identify the factors associated with reduced eGFR at diagnosis in patients with pHPT, and the determinants of longitudinal eGFR decline among those with follow-up data. Eighty-nine patients with pHPT were categorized by renal function at diagnosis. In addition, the annual eGFR decline rate was assessed in 47 patients with more than one year of follow-up. Clinical and biochemical variables were analyzed to determine their association with renal function. Compared with the normal renal function group, the reduced renal function group (eGFR <60 mL/min/1.73 m²) had higher age, and uric acid levels, lower diastolic blood pressure, daily urinary calcium (Ca) excretion, and % tubular reabsorption of phosphate (%TRP). In the multivariable logistic regression analysis, a low %TRP remained significantly associated with reduced renal function at diagnosis. Patients with an eGFR decline faster than –3 mL/min/1.73 m² per year had significantly higher serum chloride and 25-hydroxyvitamin D levels, and lower HbA1c levels than those with a slower decline. Logistic regression analysis showed, that higher serum chloride levels were associated with a faster annual decline in eGFR. In conclusion, reduced eGFR at pHPT diagnosis was associated with lower %TRP, whereas a faster annual eGFR decline was associated with higher serum chloride levels.

In order to explore if γ-secretase inhibitor can regulate γδT17 cells by blockading Notch1 signaling pathway and then affect thyroid autoimmune damage in experimental autoimmune thyroiditis (EAT) mice. Twenty-four female C57BL/6 mice, 6 to 8-week-old, were randomly divided into NC and EAT groups, and EAT group included EAT-A (pTg treated) and EAT-B (treated with DAPT before pTg) subgroups. HE staining was conducted to observe the pathological changes of thyroid tissue. ELISA was adopted to measure the concentrations of thyroglobulin antibody (TgAb) and interleukin 17A (IL-17A) in serum. The proportions of γδT17 cells were analysed by flow cytometry. The mRNA expressions of Notch1, hairy and split 1 (Hes1) and IL-17A were measured by RT-qPCR and the protein levels of Notch intracellular domain (NICD), Hes1 and IL-17A were examined by Western Blot. The titers of TgAb and IL-17A in serum, the proportions of γδT17 cells in spleen mononuclear cells (SMCs) and thyroid mononuclear cells (TMCs), the Notch1, Hes1, IL-17A mRNA and protein expressions in EAT-A mice were all increased significantly compared with NC group (all p < 0.001). However, in EAT-B group, the above indexes were all reduced significantly than those in EAT-A group (all p < 0.05), as well as the degrees of lymphocyte infiltration in thyroid were alleviated remarkably compared with EAT-A group. Additionally, γδT17 cells percentages of EAT mice were positively correlated with TgAb titers, IL-17A concentrations and Notch1 mRNA expressions. γ-secretase inhibitor is speculated to alleviate thyroid autoimmune injury in EAT by downregulating γδT17 cells via inhibition of the Notch1/Hes1 signaling pathway.

Hypertonic saline infusion and water deprivation tests are commonly used to stimulate arginine vasopressin (AVP) for the diagnosis of AVP deficiency (AVP-D); however, these procedures impose a considerable burden on patients. We aimed to develop machine learning models to predict impaired AVP secretion and thereby reduce the need for AVP stimulation testing. This retrospective cohort study included 64 patients who underwent the hypertonic saline test (HST) at Nagoya University Hospital, Japan, between 2018 and 2024. Impaired AVP secretion was defined as a predicted plasma AVP level <1.0 pg/mL at a serum sodium level of 149 mEq/L during the HST. Feature selection was performed using univariate screening and systematic selection procedures. Logistic regression and support vector machine models were developed using baseline clinical and laboratory parameters obtained before the HST and validated using nested cross-validation. The primary outcome was the area under the receiver operating characteristic curve (AUC); secondary outcomes included the sensitivity, specificity, and positive and negative predictive values. Four variables (urinary osmolality, serum sodium, plasma AVP, and blood urea nitrogen) were selected. The logistic regression model achieved an AUC of 0.862 for predicting impaired AVP secretion. Among 35 patients who underwent the HST for suspected AVP-D, at the optimized threshold, the positive and negative predictive values were 100% (14/14 patients) and 33.3% (7/21 patients), respectively. The developed machine learning model can identify a subset of patients with impaired AVP secretion without requiring the HST, potentially reducing the number of patients who need AVP stimulation testing for AVP-D diagnosis.

MIRAGE syndrome is a multisystemic disorder with a poor prognosis, caused by gain-of-function mutations in the SAMD9 gene. To date, no comprehensive reports on the systemic manifestations and management of MIRAGE syndrome in adult survivors. Here, we present the case of a 22-year-old man long-term survivor of MIRAGE syndrome with a wide range of clinical presentations and complications. From the neonatal period, he exhibited the core features of MIRAGE syndrome: myelodysplasia, recurrent infection, growth retardation, adrenal hypoplasia, atypical external genitalia, and enteropathy. Additionally, brain imaging at 5 years of age revealed new findings, including basal ganglia and white matter lesions, calcification, infarction, and ventricular enlargement. Subsequently, proteinuria was detected at 6 years of age, which gradually progressed to end-stage renal disease. At 21 years of age, he received a living-donor kidney transplant from his father, the first transplant reported for this syndrome. Genetic analysis identified a congenital SAMD9 mutation (p.Gln1286Lys) and three acquired reversion mutations. These revision mutations mitigated his hematologic complications but did not fully restore immune function. In addition to persistent immunological and endocrine dysfunction, the patient has developed progressive neurological and metabolic abnormalities over time. Multidisciplinary management, including prophylactic intravenous immunoglobulin therapy, renal replacement therapy and transplantation, and endocrine support, was provided and may have contributed to his long-term survival. This case highlights the evolving clinical spectrum of MIRAGE syndrome and underscores the importance of careful longitudinal monitoring for patients who survive beyond early childhood.

Familial partial lipodystrophy (FPLD) is a rare inherited disorder characterized by limb adipose tissue atrophy and metabolic abnormalities, including severe insulin resistance. However, diagnosis is often delayed because the characteristic physique can be difficult to recognize without a high index of suspicion. We present the case of a 19-year-old Japanese woman diagnosed with FPLD type 2 (FPLD2). She had a history of irregular menses and hirsutism since adolescence. The FPLD2 diagnosis was prompted by her concerns about axillary and inguinal pigmentation. Her mother’s online search first suggested acanthosis nigricans (AN). After including “muscular limb” as an additional search term, they suspected lipodystrophy, prompting a consultation with an endocrinologist. Clinical examination revealed impaired glucose tolerance, severe insulin resistance, dyslipidemia, fatty liver, and polycystic ovary syndrome. Genetic testing identified a heterozygous LMNA p.R482Q variant, confirming the diagnosis. This case demonstrates that AN, a skin manifestation of insulin resistance, is an important diagnostic clue for FPLD. Although women with FPLD frequently present with menstrual irregularities and hirsutism in their late teens, their insulin levels are rarely measured before diabetes onset. Consequently, the underlying severe insulin resistance is frequently overlooked. Although reported cases of FPLD2 in Japan are limited, many cases may remain undiagnosed. Therefore, clinicians should examine the friction-prone areas in non-severely obese individuals with metabolic or menstrual irregularities. The absence of AN does not rule out insulin resistance. Therefore, even without AN, the presence of other features of insulin resistance warrant consideration of FPLD and careful evaluation for limb fat loss, facilitating early diagnosis.

Sarcoidosis is a granulomatous disease that affects multiple organs; however, pituitary involvement is extremely rare. Although autoimmune diseases, such as Sjögren’s disease (SjD), may coexist, overlapping cases presenting with hypopituitarism are exceedingly rare. A 76-year-old man was admitted with hyponatremia and altered consciousness as chief complaints. Endocrine testing revealed panhypopituitarism, and magnetic resonance imaging showed pituitary gland and pituitary stalk enlargement with homogeneous enhancement. Whole-body imaging revealed extensive lymphadenopathy. Histological examination of lymph node and lung biopsy specimens revealed non-necrotizing granulomas, indicative of sarcoidosis. Salivary gland biopsy and autoantibody testing confirmed the presence of concomitant SjD. Hormone replacement therapy markedly improved pituitary enlargement and pituitary hormone secretion, allowing the discontinuation of replacement therapy after 137 days. However, despite the improvement in pituitary and lymph node lesions, interstitial pneumonia subsequently developed due to SjD, necessitating systemic immunosuppressive therapy. In conclusion, this case demonstrates a rare overlap between sarcoidosis presenting with hypopituitarism and SjD, in which pituitary lesions improved, but immune activity progressed in other organs. Thus, immune-mediated disease activity may differ between organs in overlapping syndromes, and pituitary lesions in sarcoidosis do not necessarily parallel systemic disease activity.