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Background: The growth hormone-insulin-like growth factor (GH-IGF-1) axis and its impairment with sarcopenia, frailty, bone health, complications, and prognosis are not well characterized in cirrhosis. Methods: We investigated the adult decompensated cirrhosis out-patients at a tertiary care institute between 2021 and 2023 for serum GH and IGF-1 levels, and associated them with sarcopenia (CT-SMI in cm2/m2), liver frailty index (LFI), osteodystrophy (DEXA), clinical decompensations (overall, ascites, encephalopathy, infection, and bleed), and survival up to 180 days. Results: One-hundred-seventy-two patients, 95% males, aged 46.5 years (median). logIGF-1 levels were negatively associated with sarcopenia, osteodystrophy, LFI, CTP, and MELD-Na score (P < 0.05 each). Patients with low IGF-1 levels had a higher incidence of complications (overall, ascites and encephalopathy) than those with intermediate, and high IGF-1 levels (P < 0.05 each). Both logIGF-1 (AUC: 0.686) and MELD (AUC: 0.690) could predict 180-day mortality (P < 0.05, each). Adding logIGF-1 with MELDNa further improved discriminative accuracy of MELDNa (AUC: 0.729) P < 0.001. The increase in IGF-1 on follow-up was associated with better survival and fewer complications. Conclusion: Reduced IGF-1 levels reflect sarcopenia, frailty, and osteodystrophy in cirrhosis. Low IGF-1 are associated with severity, development of decompensations, and mortality.

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Ovarian cancer, although not among the most commonly diagnosed cancers, remains a significant cause of cancer-related mortality in females. Several paraneoplastic syndromes have been associated, and this case study represents a rare manifestation of ovarian cancer, presenting as non-islet cell tumor hypoglycemia (NICTH), characterized by the excessive production of insulin-like growth factor-II (IGF-II) by tumor cells. We report a 55-year-old woman who presented to our hospital with abdominal distension and severe refractory hypoglycemia. The laboratory data revealed the suppression of serum insulin and C-peptide levels. The insulin-like growth factor II (IGF-II)/insulin-like growth factor 1 (IGF1) ratio was >32. The hypoglycemia was hence attributed to the non-islet cell tumor type, and it is likely driven by tumoral secretion of incompletely processed IGF-II. The lab findings suggested the existence of NICTH. Abdominal computed tomography demonstrated the presence of a left ovarian mass and peritoneal carcinomatosis. CT-guided biopsy of the peritoneal lesions showed poorly differentiated malignancy consistent with ovarian carcinosarcoma (OCS). The patient was treated with a continuous infusion of glucose. She even received oral prednisone and glucagon infusion. Chemotherapy with carboplatin and paclitaxel was initiated, but unfortunately, she died from complications of multiorgan failure. To our knowledge, this is the first novel case of an initial presentation of metastatic OCS with NICTH, underscoring the complexity of ovarian cancer presentations and the necessity of a comprehensive approach in managing rare paraneoplastic syndromes, such as NICTH.

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BACKGROUND: Infertility, which affects 8%-12% of couples worldwide and 21.9% of couples in Pakistan in particular, is a major reproductive health issue. In vitro fertilization (IVF) has emerged as a prevalent therapeutic intervention. Recent studies have identified insulin-like growth factor-I (IGF-I) as a promising biomarker for assessing embryo viability and predicting implantation outcomes in IVF procedures.

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Insulin-like growth factor (IGF)-I mediates long-term activities that determine cell fate, including cell proliferation and differentiation. This study aimed to characterize the mechanisms by which IGF-I determines cell fate from the aspect of IGF-I signaling dynamics. In L6 myoblasts, myogenic differentiation proceeded under low IGF-I levels, whereas proliferation was enhanced under high levels. Mathematical and experimental analyses revealed that IGF-I signaling oscillated at low IGF-I levels but remained constant at high levels, suggesting that differences in IGF-I signaling dynamics determine cell fate. We previously reported that differential insulin receptor substrate (IRS)-1 levels generate a driving force for cell competition. Computational simulations and immunofluorescence analyses revealed that asynchronous IRS-1 protein oscillations were synchronized during myogenic processes through cell competition. Disturbances of cell competition impaired signaling synchronization and cell fusion, indicating that synchronization of IGF-I signaling oscillation is critical for myoblast cell fusion to form multinucleate myotubes.

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PURPOSE: We aimed to investigate the relationship between the tri-ponderal mass index (TMI), a new indirect measure of fat mass, and insulin-like growth factor (IGF)-I/IGF binding protein (IGFBP)-3. METHODS: The study included 1,630 children and adolescents who visited Jeonbuk National University Children's Hospital. Each patient's medical record was retrospectively reviewed for age, sex, height, weight, body mass index (BMI), TMI, and IGF-1 and IGFBP-3 levels. Study participants were divided by sex and then categorized by age, BMI, and TMI. Finally, the correlations of TMI with IGF-1 level, IGF-1 standard deviation score (SDS), IGFBP-3 level, IGFBP-3 SDS, and IGF-1/IGFBP-3 ratio were investigated. RESULTS: All participants were <19 years of age. BMI correlated with IGF-1 and IGFBP-3 levels in both sexes; however, the relationship with TMI differed by sex. TMI correlated with IGF-1 and IGFBP-3 SDS in boys and with IGF-1, IGFBP-3, and IGFBP-3 SDS in girls across all ages. In boys, BMI and TMI significantly correlated with IGF-1, IGF-1 SDS, IGFBP-3, IGFBP-3 SDS, and the IGF-1/IGFBP-3 ratio in the normal-weight group. TMI also correlated with IGF-1, IGFBP-3, and IGFBP-3 SDS in the overweight group. In girls, BMI significantly correlated with IGF-1, IGF-1 SDS, IGFBP-3, IGFBP-3 SDS, and the IGF-1/IGFBP-3 ratio in the normal-weight group and with IGFBP-3 and IGFBP-3 SDS in the overweight group, while TMI correlated with IGF-1, IGF-1 SDS, and the IGF-1/IGFBP-3 ratio in the normal-weight group; with IGF-1, IGFBP-3, and IGFBP-3 SDS in the overweight group; and with IGFBP-3 SDS in the obese group. CONCLUSION: TMI may more strongly correlate with IGFBP-3 level than BMI in overweight boys and with IGFBP-3 SDS in overweight and obese girls. The correlation of IGFBP-3 SDS with TMI may be helpful for evaluating weight status in adolescent girls.

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Alzheimer's disease (AD) is the leading cause of dementia among the elderly population, posing a significant public health challenge due to limited therapeutic options that merely delay cognitive decline. AD is associated with impaired energy metabolism and reduced neurotrophic signaling. The insulin-like growth factor (IGF) signaling pathway, crucial for central nervous system (CNS) development, metabolism, repair, cognition, and emotion regulation, includes IGF-1, IGF-2, IGF-1R, IGF-2R, insulin receptor (IR), and six insulin-like growth factor binding proteins (IGFBPs). Research has identified abnormalities in IGF signaling in individuals with AD and AD models. Dysregulated expression of IGFs, receptors, IGFBPs, and disruptions in downstream phosphoinositide 3-kinase-protein kinase B (PI3K/AKT) and mitogen-activated protein kinase (MAPK) pathways collectively increase AD susceptibility. Studies suggest modulating the IGF pathway may ameliorate AD pathology and cognitive decline. This review explores the CNS pathophysiology of IGF signaling in AD progression and assesses the potential of targeting the IGF system as a novel therapeutic strategy. Further research is essential to elucidate how aberrant IGF signaling contributes to AD development, understand underlying molecular mechanisms, and evaluate the safety and efficacy of IGF-based treatments.

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Background: Doege-Potter syndrome, characterized by solitary fibrous tumors and non-islet cell tumor hypoglycemia, is rare. Here, we report a case of Doege-Potter syndrome in which retroperitoneal tumor resection was performed with continuous intraoperative blood glucose monitoring. Case presentation: A 37-year-old man presented with hypoglycemia-related symptoms, and a 10 × 12 × 9 cm tumor was found in his right kidney. Following tumor resection, insulin secretory abnormalities improved, and intraoperative blood glucose monitoring showed no hypoglycemic events. High levels of insulin-like growth factor-II confirmed the diagnosis of an insulin-like growth factor-II-producing tumor with non-islet cell tumor hypoglycemia. Postoperative serum insulin-like growth factor-II levels normalized, with no recurrence observed over 3 years. Conclusions: This case highlights the rarity of primary retroperitoneal Doege-Potter syndrome, emphasizes the safety of intraoperative blood glucose levels during surgery, and suggests rapid recovery of insulin secretion postoperatively.

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Optimal non-invasive biomarkers for metabolic dysfunction-associated steatotic liver disease (MASLD) remain elusive, especially in the detection of early stages. This study tested in an asymptomatic cohort of 171 men (49.2 ± 8.6 years) and 131 women (51.8 ± 8.5 years) whether waist circumference (WC) and circulating levels of insulin-like growth factor-binding protein 2 (IGFBP-2) could identify individuals with liver fat >5% as assessed by magnetic resonance spectroscopy. Participants with high WC (> 85 or 90 cm for women and men, respectively) and low IGFBP-2 (< 260 or 230 ng/mL for women and men, respectively) were characterized by a higher risk of having MASLD (46.3%, p < 0.0001). Among the 68 individuals with MASLD, 73.5% fell into the subgroup with high WC and low IGFBP-2 concentrations (p < 0.0001). When combined, these markers reached a sensitivity of 73.5% and specificity of 75.2% for MASLD. Thus, WC and plasma IGFBP-2 levels might be useful as a novel, simple, and non-invasive index to support existing tools in the identification of individuals at risk of early-stage MASLD.

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Crosstalk between cancer-associated fibroblasts (CAFs) and tumour cells plays a critical role in multiple cancers, including hepatocellular carcinoma (HCC). CAFs contribute to tumorigenesis by secreting growth factors, modifying the extracellular matrix, supporting angiogenesis, and suppressing antitumor immune responses. However, effect and mechanism of CAF-mediated promotion of hepatocellular carcinoma cells are still unclear. In study, we demonstrated CAFs promoted the proliferation and inhibited the apoptosis of HCC cells by secreting interleukin-6 (IL-6), which induced autocrine insulin-like growth factor-1 (IGF-1) in HCC. IGF-1 promoted the progression and chemoresistance of HCC. IGF-1 receptor (IGF-1R) inhibitor NT157 abrogated the effect of CAF-derived IL-6 and autocrine IGF-1 on HCC. Mechanistic studies revealed that NT157 decreased IL-6-induced IGF-1 expression by inhibiting STAT3 phosphorylation and led to IRS-1 degradation, which mediated the proliferation of tumour by activating AKT signalling in ERK-dependent manner. Inhibition of IGF-1R also enhanced the therapeutic effect of sorafenib on HCC, especially chemoresistant tumours. STATEMENT OF SIGNIFICANCE: Our study showed IL-6-IGF-1 axis played crucial roles in the crosstalk between HCC and CAFs, providing NT157 inhibited of STAT3 and IGF-1R as a new targeted therapy in combination with sorafenib.

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Mitochondria play a critical role in follicular development and ovulation, at least in part through the actions of growth hormone (GH)/insulin-like growth factor-1 (IGF-1) on mitochondrial biogenesis. This study aimed to identify seasonal alterations in the GH/IGF-1 system and mitochondrial biogenesis in muskrat (Ondatra zibethicus) ovaries. We utilized the muskrat, a typical seasonal breeder, to clarify the potential impact of the GH/IGF-1 system on mitochondrial biogenesis across different breeding seasons using immunohistochemistry, gene expression and high-throughput sequencing. Alterations in follicular development existed in muskrat ovaries between the breeding season (BS) and non-breeding season (NBS), accompanied by a striking decrease in circulating and ovarian GH and IGF-1 concentrations. GH, GHR, IGF-1, IGF-1R, and mitochondrial biogenesis markers were localized in the ovarian cells of muskrats during both seasons. In contrast, Gh, Ghr, Igf-1, Igf-1r, Ppargc1a, Ppargc1b, Tfam, and Nrf1/2 mRNA levels were higher in BS. The relative levels of GH and IGF-1 in circulation and ovaries were positively associated with mitochondrial biogenesis markers. Additionally, RNA-seq analysis demonstrated that differentially expressed genes might be associated with insulin and PI3K/Akt signaling pathways, as well as mitochondrial function-related pathways. These findings suggest that the intra-ovarian GH/IGF-1 system, which is associated with seasonal changes in mitochondrial biogenesis, is activated in muskrat ovaries in BS.

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Insulin-like Growth Factor-1 (IGF-1) is a crucial mitogenic factor with important functions in the mammary gland, mainly through its interaction with the IGF-1 receptor (IGF-1R). This interaction activates a complex signaling network that promotes cell proliferation, epithelial to mesenchymal transition (EMT) and inhibits apoptosis. Despite extensive research, the precise molecular pathways and intracellular mechanisms activated by IGF-1, in cancer, remain poorly understood. Recent evidence highlights the essential roles of IGF-1 and its isoforms in breast cancer (BC) development, progression, and metastasis. The peptides that define the IGF-1 isoforms-IGF-1Ea, IGF-1Eb, and IGF-1Ec-act as key points of convergence for various signaling pathways that influence the growth, metastasis and survival of BC cells. The aim of this review is to provide a detailed exami-nation of the role of the mature IGF-1 and its isoforms in BC biology and their potential use as possible therapeutical targets.

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BACKGROUND: Hepatocellular adenoma (HCA) is a rare benign neoplasm, seldom ascribed as the cause of endocrine and metabolic derangement. We herein report a case of primary amenorrhea, growth arrest and metabolic syndrome. En bloc resection of the tumor normalized all the disturbances. CASE PRESENTATION: A 16-year-old girl complained of primary amenorrhea and growth arrest for the past 2 years. Her height and weight were at the 3rd percentile, whereas waist circumference was at the 90th percentile for chronological age. She was hypertensive on admission. Plasma cholesterol, triglyceride and uric acid were elevated. Evaluation of GH/IGF-1 axis showed extremely low IGF-1 concentration, which was unresponsive to hGH stimulation. Computer tomography identified a huge liver mass (18.2 cm×13.7 cm×21 cm). The patient underwent an uneventful open right hepatic lobectomy. The tumor was en bloc resected. Immunohistochemistry indicated an unclassified HCA, which was confirmed by genetic screening. IGF-1 concentration, blood pressure, lipid profile and ovarian function were all normalized after surgery, and the girl had reduction in waist circumference and gain in height during the follow up. CONCLUSION: We provide evidence that liver-derived IGF-1 has a direct effect on skeletal and pubertal development, blood pressure, visceral adiposity and dyslipidemia independent of insulin resistance and obesity in the circumstance of undernutrition. Though rare, we propose the need to look into HCA cases for the existence of IGF-1 deficiency and its impact on metabolic derangement.

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Mir483 is a conserved and highly expressed microRNA in placental mammals, embedded within the Igf2 gene. Its expression is dysregulated in a number of human diseases, including metabolic disorders and certain cancers. Here, we investigate the developmental regulation and function of Mir483 in vivo. We find that Mir483 expression is dependent on Igf2 transcription and the regulation of the Igf2/H19 imprinting control region. Transgenic Mir483 overexpression in utero causes fetal, but not placental, growth restriction through insulin-like growth factor 1 (IGF1) and IGF2 and also causes cardiovascular defects leading to fetal death. Overexpression of Mir483 post-natally results in growth stunting through IGF1 repression, increased hepatic lipid production, and excessive adiposity. IGF1 infusion rescues the post-natal growth restriction. Our findings provide insights into the function of Mir483 as a growth suppressor and metabolic regulator and suggest that it evolved within the INS-IGF2-H19 transcriptional region to limit excessive tissue growth through repression of IGF signaling.

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CONTEXT: Somapacitan, a once-weekly reversible albumin-binding GH derivative, is evaluated in short children born small for gestational age (SGA). OBJECTIVE: Evaluate efficacy, safety, tolerability as well as total and bioactive insulin-like growth factor-I (IGF-I) response of once-weekly somapacitan compared to daily GH in children born SGA. METHODS: REAL5 is a randomized, multi-center, open-label, controlled phase 2 study comprising a 26-week main phase, 26-week extension, and an ongoing 4-year safety extension (NCT03878446). SETTING: Thirty-eight sites across 12 countries. PATIENTS: Sixty-two GH-treatment-naïve, prepubertal short children born SGA were randomized; 61 completed 52-weeks of treatment. INTERVENTIONS: Patients randomized (1:1:1:1:1) to somapacitan (0.16, 0.20 or 0.24 mg/kg/week) or daily GH (0.035 or 0.067 mg/kg/day), all administered subcutaneously. RESULTS: Estimated mean height velocity (HV; cm/year) at week 52 was 8.5, 10.4 and 10.7 cm/year for somapacitan 0.16, 0.20 and 0.24 mg/kg/week, respectively, and 9.3 and 11.2 cm/year for daily GH 0.035 and 0.067 mg/kg/day, respectively. Dose-dependent increases in total IGF-I as well as peak IGF-I bioactivity were observed for both treatments and were similar between comparator groups. For somapacitan, exposure-response modelling indicated highest efficacy with 0.24 mg/kg/week after 52 weeks of treatment. Similar safety and tolerability were demonstrated across all groups. CONCLUSIONS: A sustained dose-dependent growth response was demonstrated for somapacitan after 52 weeks of treatment. Overall, somapacitan 0.24 mg/kg/week provides similar efficacy, safety, and tolerability, as well as comparable bioactive and total IGF-I response, as daily GH (0.067 mg/kg/day) in children born SGA.

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Aging is closely associated with various cerebrovascular pathologies that significantly impact brain function, with cerebral small vessel disease (CSVD) being a major contributor to cognitive decline in the elderly. Consequences of CSVD include cerebral microhemorrhages (CMH), which are small intracerebral bleeds resulting from the rupture of microvessels. CMHs are prevalent in aging populations, affecting approximately 50% of individuals over 80, and are linked to increased risks of vascular cognitive impairment and dementia (VCID). Hypertension is a primary risk factor for CMHs. Vascular smooth muscle cells (VSMCs) adapt to hypertension by undergoing hypertrophy and producing extracellular matrix (ECM) components, which reinforce vessel walls. Myogenic autoregulation, which involves pressure-induced constriction, helps prevent excessive pressure from damaging the vulnerable microvasculature. However, aging impairs these adaptive mechanisms, weakening vessel walls and increasing susceptibility to damage. Insulin-like Growth Factor 1 (IGF-1) is crucial for vascular health, promoting VSMC hypertrophy, ECM production, and maintaining normal myogenic protection. IGF-1 also prevents microvascular senescence, reduces reactive oxygen species (ROS) production, and regulates matrix metalloproteinase (MMP) activity, which is vital for ECM remodeling and stabilization. IGF-1 deficiency, common in aging, compromises these protective mechanisms, increasing the risk of CMHs. This review explores the vasoprotective role of IGF-1 signaling in the cerebral microcirculation and its implications for preventing hypertension-induced CMHs in aging. Understanding and addressing the decline in IGF-1 signaling with age are crucial for maintaining cerebrovascular health and preventing hypertension-related vascular injuries in the aging population.

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Despite therapy with growth hormone (GH) in children with Prader-Willi syndrome (PWS), low bone mineral density and various orthopedic deformities have been observed often. Therefore, this study aimed to analyze bone markers, with an emphasis on vitamin K-dependent proteins (VKDPs), in normal-weight children with PWS undergoing GH therapy and a low-energy dietary intervention. Twenty-four children with PWS and 30 healthy children of the same age were included. Serum concentrations of bone alkaline phosphatase (BALP), osteocalcin (OC), carboxylated-OC (Gla-OC), undercarboxylated-OC (Glu-OC), periostin, osteopontin, osteoprotegerin (OPG), sclerostin, C-terminal telopeptide of type I collagen (CTX-I), and insulin-like growth factor-I (IGF-I) were determined using immunoenzymatic methods. OC levels and the OC/CTX-I ratios were lower in children with PWS than in healthy children (p = 0.011, p = 0.006, respectively). Glu-OC concentrations were lower (p = 0.002), but Gla-OC and periostin concentrations were higher in patients with PWS compared with the controls (p = 0.005, p < 0.001, respectively). The relationships between IGF-I and OC (p = 0.013), Gla-OC (p = 0.042), and the OC/CTX-I ratio (p = 0.017) were significant after adjusting for age in children with PWS. Bone turnover disorders in children with PWS may result from impaired bone formation due to the lower concentrations of OC and the OC/CTX-I ratio. The altered profile of OC forms with elevated periostin concentrations may indicate more intensive carboxylation processes of VKDPs in these patients. The detailed relationships between the GH/IGF-I axis and bone metabolism markers, particularly VKDPs, in children with PWS requires further research.

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Obesity is characterized by the chronic low-grade activation of the innate immune system. In this respect, macrophage-elicited metabolic inflammation and adipocyte-macrophage interaction have primary importance in obesity. Large quantity of macrophages is accumulated by different mechanisms in obese adipose tissue. Hypertrophic adipocyte-derived chemotactic monocyte chemoattractant protein-1 (MCP-1)/C-C chemokine receptor 2 (CCR2) pathway promotes more macrophage accumulation into the obese adipose tissue. However, obesity-induced changes in adipose tissue macrophage density are mainly dependent on increases in the triple-positive cluster of differentiation (CD)11b+ F4/80+ CD11c+ adipose tissue macrophage subpopulation. As epigenetic regulators, microRNAs (miRNAs) are one of the most important mediators of obesity. miRNAs are expressed by adipocytes as well as macrophages and regulate inflammation with the expression of target genes. A paracrine loop involving free fatty acids and tumor necrosis factor-alpha (TNF-α) between adipocytes and macrophages establishes a vicious cycle that aggravates inflammatory changes in the adipose tissue. Adipocyte-specific caspase-1 and production of interleukin-1beta (IL-1ß) by macrophages; both adipocyte and macrophage induction by toll-like receptor-4 (TLR4) through nuclear factor-kappaB (NF-κB) activation; free fatty acid-induced and TLR-mediated activation of c-Jun N-terminal kinase (JNK)-related pro-inflammatory pathways in CD11c+ immune cells; are effective in mutual message transmission between adipocyte and macrophage and in the development of adipose tissue inflammation. Thus, the metabolic status of adipocytes and their released exosomes are important determinants of macrophage inflammatory output. However, old adipocytes are removed by macrophages through trogocytosis or sending an "eat me" signal. As a single miRNA can be able to regulate a variety of target genes and signaling pathways, reciprocal transfer of miRNAs between adipocytes and macrophages via miRNA-loaded exosomes reorganizes the different stages of obesity. Changes in the expression of circulating miRNAs because of obesity progression or anti-obesity treatment indicate that miRNAs could be used as potential biomarkers. Therefore, it is believed that targeting macrophage-associated miRNAs with anti-obesity miRNA-loaded nano-carriers may be successful in the attenuation of both obesity and adipose tissue inflammation in clinical practice. Moreover, miRNA-containing exosomes and transferable mitochondria between the adipocyte and macrophage are investigated as new therapeutic targets for obesity-related metabolic disorders.

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Several studies show that a significantly stronger association is obvious between increased body mass index (BMI) and higher breast cancer incidence. Additionally, obese and postmenopausal women are at higher risk of all-cause and breast cancer-specific mortality compared with non-obese women with breast cancer. In this context, increased levels of estrogens, excessive aromatization activity of the adipose tissue, overexpression of pro-inflammatory cytokines, insulin resistance, adipocyte-derived adipokines, hypercholesterolemia, and excessive oxidative stress contribute to the development of breast cancer in obese women. Genetic evaluation is an integral part of diagnosis and treatment for patients with breast cancer. Despite trimodality therapy, the four-year cumulative incidence of regional recurrence is significantly higher. Axillary lymph nodes as well as primary lesions have diagnostic, prognostic, and therapeutic significance for the management of breast cancer. In clinical setting, because of the obese population primary lesions and enlarged lymph nodes could be less palpable, the diagnosis may be challenging due to misinterpretation of physical findings. Thereby, a nomogram has been created as the "Breast Imaging Reporting and Data System" (BI-RADS) to increase agreement and decision-making consistency between mammography and ultrasonography (USG) experts. Additionally, the "breast density classification system," "artificial intelligence risk scores," ligand-targeted receptor probes," "digital breast tomosynthesis," "diffusion-weighted imaging," "18F-fluoro-2-deoxy-D-glucose positron emission tomography," and "dynamic contrast-enhanced magnetic resonance imaging (MRI)" are important techniques for the earlier detection of breast cancers and to reduce false-positive results. A high concordance between estrogen receptor (ER) and progesterone receptor (PR) status evaluated in preoperative percutaneous core needle biopsy and surgical specimens is demonstrated. Breast cancer surgery has become increasingly conservative; however, mastectomy may be combined with any axillary procedures, such as sentinel lymph node biopsy (SLNB) and/or axillary lymph node dissection whenever is required. As a rule, SLNB-guided axillary dissection in breast cancer patients who have clinically axillary lymph node-positive to node-negative conversion following neoadjuvant chemotherapy is recommended, because lymphedema is the most debilitating complication after any axillary surgery. There is no clear consensus on the optimal treatment of occult breast cancer, which is much discussed today. Similarly, the current trend in metastatic breast cancer is that the main palliative treatment option is systemic therapy.

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Reduced fibroblast activity is a critical factor in the progression of diabetic ulcers. CD248, a transmembrane glycoprotein prominently expressed in activated fibroblasts, plays a pivotal role in wound healing. However, the role of CD248 in diabetic wound healing and the CD248 regulatory pathway remains largely unexplored. Our study shows that CD248 expression is significantly reduced in skin wounds from both diabetic patients and mice. Single-cell transcriptome data analyses reveal a marked reduction of CD248-enriched secretory-reticular fibroblasts in diabetic wounds. We identify insulin-like growth factor-1 (IGF-1) as a key regulator of CD248 expression through the Akt/mTOR signaling pathway and the Sp1 transcription factor. Overexpression of CD248 enhances fibroblast motility, elucidating the underrepresentation of CD248-enriched fibroblasts in diabetic wounds. Immunohistochemical staining of diabetic wound samples further confirm low SP1 expression and fewer CD248-positive secretory-reticular fibroblasts. Further investigation reveals that elevated tumor necrosis factor α (TNFα) levels in diabetic environment promotes IGF-1 resistance, and inhibiting IGF-1-induced CD248 expression. In summary, our findings underscore the critical role of the IGF1-SP1-CD248 axis in activating reticular fibroblasts during wound-healing processes. Targeting this axis in fibroblasts could help develop a therapeutic regimen for diabetic ulcers.