Molecular And Cellular Endocrinology[JOURNAL]
Sun
200 papers
Inhibition of RGS1 ameliorates obesity-associated macrophage dysfunction and metaflammation through restoration of PINK1/Parkin-mediated mitophagy.
Li Y, Fu X, Yin B … +2 more , Nasrin M, Huo R
Mol Cell Endocrinol · 2026 Sep · PMID 42134621 · Publisher ↗
BACKGROUND: Obesity-associated metabolic inflammation is characterized by the infiltration and pro-inflammatory polarization of adipose tissue macrophages (ATMs). Mitochondrial dysfunction represents a central pathogenic...
BACKGROUND: Obesity-associated metabolic inflammation is characterized by the infiltration and pro-inflammatory polarization of adipose tissue macrophages (ATMs). Mitochondrial dysfunction represents a central pathogenic mechanism; however, the upstream molecular mechanisms that link metabolic stress to impaired mitochondrial quality control in macrophages remain inadequately defined. Regulator of G protein signaling 1 (RGS1) is significantly upregulated in ATMs under obese conditions; nevertheless, its functional role and mechanistic relevance have not been fully elucidated. METHODS: Integrated transcriptomic analyses identified RGS1 as a pivotal gene associated with obesity, and its expression profiles in adipose tissue macrophages were analyzed by integrating single-cell RNA sequencing data from humans and mice. In vivo, immunohistochemistry and immunofluorescence assessed RGS1 localization in adipose tissue from high-fat diet-fed obese mice. In vitro, RAW264.7 cells and bone marrow-derived macrophages (BMDMs) were treated with palmitic acid (PA) or PA plus interleukin-6 (IL-6), combined with lentivirus-mediated RGS1 knockdown. The effects of RGS1 on mitochondrial integrity, mitophagic flux, lipid metabolism, and macrophage polarization were assessed by Western blot, quantitative real-time PCR, transmission electron microscopy, TMRE staining, reactive oxygen species (ROS) production, ATP levels, and oxidative phosphorylation (OXPHOS). Furthermore, bafilomycin A1 (Baf-A1) was used to assess mitophagic flux, and Mdivi-1 was utilized to inhibit mitophagy for mechanistic validation. RESULTS: Bioinformatic analyses revealed a significant upregulation of RGS1 in ATMs under obese conditions. In vivo studies demonstrated elevated levels of RGS1 in the epididymal adipose tissue of obese mice, where it co-localized with CD86 M1 macrophages. In vitro, PA treatment induced RGS1 expression and caused lipid accumulation and M1 macrophage polarization; co-stimulation with PA and interleukin-6 (IL-6) further upregulated RGS1 and exacerbated pro-inflammatory responses. Conversely, RGS1 knockdown markedly attenuated both lipid accumulation and M1 polarization. Furthermore, PA treatment induced severe mitochondrial dysfunction, characterized by cristae disruption, loss of membrane potential, ROS accumulation, ATP depletion, and decreased expression of OXPHOS complexes, and inhibited PINK1/Parkin-mediated mitophagy. In contrast, RGS1 knockdown restored mitochondrial function. Baf-A1 treatment assays confirmed that RGS1 knockdown augmented mitophagic flux, while treatment with Mdivi-1 significantly diminished this protective effect, indicating that these protective effects were likely mediated in a mitophagy-dependent manner. CONCLUSION: RGS1 acts as a critical switch linking metabolic stress to macrophage dysfunction. Targeting RGS1 may represent a promising therapeutic strategy for alleviating obesity-induced inflammation.
Spatiotemporal complexity and druggability of PTH1R: insights from small molecules and peptides.
Vilardaga JP, Heredero-Jimenez S
Mol Cell Endocrinol · 2026 Sep · PMID 42119631 · Publisher ↗
The parathyroid hormone type 1 receptor (PTH1R) is a class B GPCR that plays a vital role in calcium and phosphate homeostasis, bone turnover, and skeletal growth. It serves as a paradigmatic model for studying the spati...
The parathyroid hormone type 1 receptor (PTH1R) is a class B GPCR that plays a vital role in calcium and phosphate homeostasis, bone turnover, and skeletal growth. It serves as a paradigmatic model for studying the spatial and temporal aspects of GPCR signaling, especially the prolonged cAMP signaling from endosomes and ligand-dependent location-biased agonism. Here, we review how small molecules and engineered peptides are advancing both the mechanistic understanding of this complex signaling process and its physiological significance, as well as drug discovery at PTH1R. Key developments include the orally administered small Gs-biased agonist PCO371, which binds the intracellular transmembrane region of the receptor; the negative non-peptidic allosteric modulator Pitt12, which decreases PTH-induced cAMP from an extracellular receptor vestibule; backbone-modified, conformationally selective peptides, which have dissected and advanced our understanding of the mechanism and biological relevance of endosomal cAMP signaling. Together, these tools are clarifying the structural basis of signaling bias and PTH1R's druggability, thereby enabling the development of therapies for bone and mineral diseases.
Gonadotropin-inhibitory hormone (GnIH) induces glycolipid metabolic dysfunction in porcine ovarian granulosa cells via Wnt and AMPK signaling pathways.
Peng K, Zhang X, Lu M … +18 more , Zhu H, Song X, Lao J, Wang W, Tang G, Ma J, Li J, Lu Y, Li L, Zhang X, Li Z, Wang Z, Li J, Wei Y, Zheng J, Wang X, Hu C, Li X
Mol Cell Endocrinol · 2026 Sep · PMID 42106142 · Publisher ↗
Animal reproduction is closely linked to energy metabolism, and ovarian glycolipid metabolism disorders can lead to follicular abnormalities, reduced fertility, and infertility. Granulosa cells (GCs), as key energy suppl...
Animal reproduction is closely linked to energy metabolism, and ovarian glycolipid metabolism disorders can lead to follicular abnormalities, reduced fertility, and infertility. Granulosa cells (GCs), as key energy suppliers in the ovary, directly influence oocyte development, hormone secretion, and reproductive function. However, the interaction between reproductive regulatory factors and ovarian energy metabolism is unclear. Our prior studies showed that gonadotropin-inhibitory hormone (GnIH) causes ovarian degeneration and glycolipid metabolism disorders in female piglets, but its ovarian-level mechanism remains unknown. We explored GnIH's effects on porcine ovarian and GC glycolipid metabolism via in vivo and in vitro experiments. In vivo, intraperitoneal GnIH (0.1, 1 mg/mL) administered for 14 days inhibited glucose transport and gluconeogenesis, but promoted glycolysis, fatty acid synthesis, and β-oxidation. It inhibited the AKT-GSK-3β pathway and activated AMPK, causing abnormal glucose to use and ATP deficiency. Metabolomics showed increased adenosine and D-glyceroldehyde 3-phosphate, and decreased citrate, glucuronic acid, and testosterone. In vitro, transcriptomics revealed 5253 differentially expressed genes (956 glycolipid-related) in GnIH-treated GCs, enriched in Wnt and AMPK pathways. GnIH promoted glucose transport, glycolysis, and glycogen synthesis while simultaneously inhibiting mitochondrial ATP synthesis - effects that were closely associated with the activation of the Wnt signaling pathway and the inhibition of the AMPK pathway. GnIH inhibited AMPK and activated Wnt, promoting glucose transport and glycolysis but suppressing mitochondrial ATP synthesis. Furthermore, functional intervention experiments demonstrated that GnIH effectively reversed the metabolic effects induced by either the AMPK activator AICAR or the Wnt inhibitor IWP2 in GCs, reinforcing that GnIH acts as a dominant regulator upstream of both pathways. In addition, GnIH exacerbated oxidative stress, induced insulin resistance, and disrupted mitochondrial dynamics. In conclusion, GnIH disrupts energy metabolism via Wnt and AMPK pathways, causing GC glycolipid disorders and dysfunction, offering new targets for reproductive disorder interventions.
Targeting melanocortin-4 receptor (MC4R) family in goldfish (Carassius auratus) for enhanced growth and optimized lipid distribution.
Mo H, Lv B, Liu Y … +9 more , Yu H, Du Y, Wang X, Gao J, Yao M, Zhang Q, Yu J, Li Y, Wang L
Mol Cell Endocrinol · 2026 Sep · PMID 42106141 · Publisher ↗
Controlling abdominal fat accumulation and appetite have consistently been key research priorities in aquaculture. The melanocortin-4 receptor (MC4R) plays a crucial role in regulating appetite and lipid metabolism. In t...
Controlling abdominal fat accumulation and appetite have consistently been key research priorities in aquaculture. The melanocortin-4 receptor (MC4R) plays a crucial role in regulating appetite and lipid metabolism. In teleost fish, such as goldfish, there are two or more homologs of MC4R, yet the functions and significance of these homologs remain incompletely understood. To address this, we chose goldfish as a model organism and investigated the functions of caMC4R (Carassius auratus MC4R) and caMC4R-like using molecular docking, RNA interference (RNAi) and RNA sequencing (RNA-seq). Our findings indicate that the third intracellular loop (ICL3) of caMC4R and caMC4R-like differs significantly, resulting in distinct activation of cAMP signaling downstream of the receptor. The knockdown of caMC4R/caMC4R-like promoted appetite and growth in goldfish. Interestingly, the knockdown of caMC4R enhanced muscle lipid accumulation by regulating the expression of pyruvate dehydrogenase (E1) component subunit beta (PDHB). The knockdown of caMC4R-like promoted hepatic lipid accumulation via the PPARγ and SREBP-1c pathways. Overall, the knockdown of caMC4R and caMC4R-like promoted lipid accumulation in the muscle and liver of goldfish, respectively. The results of this study will provide foundational data for investigating the functions of the MC4R subfamily in teleost fish and the significance of genome duplication in fish evolution. In addition, our findings offer actionable insights for enhancing growth performance and modulating body composition in cultured fish populations, offering tangible applications for both nutritional programming and selective breeding in aquaculture production systems.
MiR-221-3p facilitates cutaneous wound healing in diabetic mice.
Wang Y, Pei J, Dai Y … +5 more , Ma Y, Tang S, Shen B, Zhang Q, Hu K
Mol Cell Endocrinol · 2026 Sep · PMID 42103008 · Publisher ↗
The persistent non-healing of cutaneous wounds in diabetic patients represents a critical clinical challenge requiring urgent resolution. Excessive inflammation, impaired angiogenesis, and aberrant collagen remodeling pr...
The persistent non-healing of cutaneous wounds in diabetic patients represents a critical clinical challenge requiring urgent resolution. Excessive inflammation, impaired angiogenesis, and aberrant collagen remodeling profoundly hinder wound recovery. This study explores the potential therapeutic value of miR-221-3p in diabetic cutaneous wound healing using murine models. Subcutaneous administration of miR-221-3p was associated with accelerated wound closure; histological staining and Western blot analyses showed decreased expression of inflammatory markers (IL-1β, IL-6, MPO, CD68), increased levels of angiogenic markers (CD31, VEGFA), and enhanced collagen I/III deposition at wound margins. Complementary experiments using Mir221 knockout mice showed delayed healing, which was accompanied by upregulated MPO/CD68 expression, reduced CD31 levels, and decreased collagen fiber formation. These bidirectional observations suggest that miR-221-3p may contribute to diabetic wound healing, potentially through effects on inflammatory responses, neovascularization, and collagen synthesis. These findings suggest that miR-221-3p could serve as a potential therapeutic target for refractory wounds in diabetic patients, including diabetic foot ulcers and other chronic cutaneous lesions.
Aerobic exercise attenuates cardiac fibrosis in mice via stimulating vitamin D receptor to suppress ferroptosis.
Cui XN, Lu SQ, Liu JJ … +5 more , Wang K, Zhang JH, Niu YJ, Zhu Z, Cao ZB
Mol Cell Endocrinol · 2026 Sep · PMID 42097528 · Publisher ↗
Aerobic exercise attenuates cardiac fibrosis in vitamin D-deficient (VDD) mice, the precise mechanism remains unclear. This study explored the potential mechanism underlying aerobic exercise-associated myocardial fibrosi...
Aerobic exercise attenuates cardiac fibrosis in vitamin D-deficient (VDD) mice, the precise mechanism remains unclear. This study explored the potential mechanism underlying aerobic exercise-associated myocardial fibrosis improvement. The VDD mouse model was successfully established after 12 weeks of dietary intervention with a 0 IU/kg vitamin D diet. Eight vitamin D-sufficient mice served as the control group (C; 1000 IU/kg vitamin D), and thirty-two VDD mice were randomly reassigned to VDD group (0 IU/kg vitamin D), VDD + exercise group (VDDE; 0 IU/kg vitamin D), VDD + vitamin D supplementation group (VDDS; 10,000 IU/kg vitamin D), and VDD + vitamin D supplementation + exercise group (VDDSE; 10,000 IU/kg vitamin D). Mice assigned to the VDDE and VDDSE groups underwent aerobic treadmill exercise training. All interventions lasted 12 weeks. VDD mice exhibited decreased myocardial vitamin D receptor (VDR) expression and fibrosis, along with the suppressed Nrf2/GPX4 pathway, mitochondrial abnormalities, and existence of ferroptosis. Aerobic exercise and vitamin D supplementation elevated VDR expression and reversed the forementioned detrimental changes. We employed adeno-associated virus (AAV) to construct the cardiac-specific VDR-knockdown mice. Mice injected with AAV-shRNA (NC) were used as control, while mice injected with AAV-shRNA (VDR) were divided into shVDR group and shVDR + exercise group. The shVDR group exhibited significant myocardial fibrosis, accompanied by suppression of the Nrf2/GPX4 pathway and appearance of ferroptosis. Aerobic exercise could not activate the Nrf2/GPX4 pathway nor suppress the expression of ferroptosis and fibrosis-related factors in the shVDR mice, resulting in a weakened effect on alleviating myocardial fibrosis. In summary, aerobic exercise attenuates cardiac fibrosis partially through the VDR/Nrf2/GPX4 pathway to inhibit ferroptosis.
Melatonin maintains human umbilical vein endothelial cells function through potential regulation of the AKT-mTOR signaling pathway involving SIRT7 in preeclampsia.
Zhou Y, Sun G, Gao Y … +2 more , Shan N, Qi H
Mol Cell Endocrinol · 2026 Sep · PMID 42097527 · Publisher ↗
INTRODUCTION: Preeclampsia (PE), known for its association with oxidative stress, can lead to impaired endothelial function. Although melatonin, as an antioxidant, has been used for treating PE, the specific mechanism un...
INTRODUCTION: Preeclampsia (PE), known for its association with oxidative stress, can lead to impaired endothelial function. Although melatonin, as an antioxidant, has been used for treating PE, the specific mechanism underlying its therapeutic effect remains ambiguous. The aim of this study is to investigate the correlation between melatonin and PE, and explore the mechanism by which melatonin enhances endothelial cell function in PE. MATERIAL AND METHODS: Serum melatonin levels were quantified by enzyme-linked immunoassay (ELISA), whereas the expression levels of melatonin receptor and sirtuin 7 (SIRT7) in the placental tissues were assessed via western blotting (WB) in both normal and preeclamptic pregnant women. The impact of melatonin on hypoxia-reoxygenation (H/R)-treated wild-type and SIRT7-knockdown human umbilical vein endothelial cells (HUVECs) was evaluated, along with the modulation of SIRT7 expression and the Protein kinase B/mammalian target of rapamycin (AKT/mTOR) signaling pathway. RESULTS: We observed a reduction in melatonin levels in patients with PE as well as decreased expression of melatonin receptor type 1A (MTNR-1A) and SIRT7 within placenta. Melatonin restored the migration and tube formation abilities and the expression level of SIRT7 in a PE cell model of HUVECs, while this restorative function was abolished upon SIRT7 knockdown. Furthermore, the AKT/mTOR signaling pathway was suppressed following H/R treatment, a phenomenon that was also observed upon SIRT7 knockdown. Conversely, melatonin administration activated the AKT/mTOR signaling pathway. CONCLUSIONS: Our results indicate a potential correlation between melatonin and the incidence of PE. Melatonin alleviates preeclampsia-related endothelial dysfunction, and this effect is associated with SIRT7 and the AKT/mTOR pathway.
Cell models for investigating adipocyte differentiation and adipogenesis: a comprehensive updated review.
Núñez-Sánchez JA, Moreno-Cañadas R, Brandimonte-Hernández M … +3 more , Gomez-Llorente C, Aguilera CM, Ruiz-Ojeda FJ
Mol Cell Endocrinol · 2026 Sep · PMID 42092449 · Publisher ↗
The prevalence of obesity and its metabolic consequences have prompted researchers to pay more attention to adipose tissue biology, the mechanisms driving adipocyte proliferation, and the process of adipogenesis. The dev...
The prevalence of obesity and its metabolic consequences have prompted researchers to pay more attention to adipose tissue biology, the mechanisms driving adipocyte proliferation, and the process of adipogenesis. The development of diverse in vitro cell models and molecular biology techniques has made it possible to investigate adipocyte commitment and differentiation, which are complex processes underlying adipose tissue function. These approaches enable a better understanding of adipocyte dysfunction and adipogenesis associated with obesity and its metabolic complications. To mimic white, beige, and brown adipocytes, researchers have established different cell models from animals and humans with adipogenic capacity. In this review, we have compiled and updated information on animal and human cell culture models used to study in vitro adipogenesis, including their main characteristics, protocols, and applications. We provide practical guidance on model selection for specific obesity-related questions such as insulin resistance, inflammation, browning, and depot-specific dysfunction. Additionally, we discuss co-cultures and three-dimensional culture systems, highlighting their value in creating a more physiological environment and elucidating the interactions between adipocytes and neighboring cells.
Copper regulates the synthesis of steroid hormones through CCS and ATOX1 dependent MEK1-ERK1/2 pathway in follicular granulosa cells of yak (Bos grunniens).
Lou Y, Yang T, Xia C … +6 more , Yang S, Deng H, Zhu Y, Fang J, Zuo Z, Guo H
Mol Cell Endocrinol · 2026 Sep · PMID 42082145 · Publisher ↗
Steroid hormone synthesis in granulosa cells (GCs) is crucial for normal follicular development and ovulation. Emerging evidence suggests that copper (Cu), a trace element, influences hormone secretion in yak granulosa c...
Steroid hormone synthesis in granulosa cells (GCs) is crucial for normal follicular development and ovulation. Emerging evidence suggests that copper (Cu), a trace element, influences hormone secretion in yak granulosa cells (YGCs); however, the underlying mechanisms remain unclear. In this study, we demonstrated that Cu supplementation upregulates estradiol (E2) and progesterone (P4) secretion in YGCs through the activation of the MEK1-ERK1/2 signaling pathway. Our findings indicate that the Cu chaperones ATOX1 and CCS, but not the Cu-dependent enzyme LOX, are essential for Cu-induced MEK1-ERK1/2 activation and subsequent hormone secretion. Gene silencing of ATOX1 or CCS resulted in reduced MEK1-ERK1/2 phosphorylation and steroidogenesis, highlighting their regulatory roles in this pathway. Although LOX influenced hormone secretion, it did not affect MEK-ERK phosphorylation, suggesting a MEK-independent mechanism. These findings reveal that Cu regulates steroid hormone synthesis in YGCs via a CCS- and ATOX1-dependent MEK1-ERK1/2 pathway, providing new insights into the molecular basis of Cu-associated reproductive disorders in yaks.
RIPK4 knockout enhances the antitumor effects of melatonin pretreatment in melanoma cells in vitro and in a xenograft model in zebrafish.
Gazda A, De Paolo R, Poliseno L … +3 more , Prajsnar TK, Kleszczyński K, Wolnicka-Glubisz A
Mol Cell Endocrinol · 2026 Aug · PMID 42061551 · Publisher ↗
Melanoma is an aggressive skin cancer characterized by high metastatic potential and resistance to conventional therapies. Melatonin, a neurohormone known for its circadian and antioxidant functions, has demonstrated ant...
Melanoma is an aggressive skin cancer characterized by high metastatic potential and resistance to conventional therapies. Melatonin, a neurohormone known for its circadian and antioxidant functions, has demonstrated anti-proliferative and pro-apoptotic effects in melanoma through both receptor-dependent and receptor-independent mechanisms. Receptor-interacting protein kinase 4 (RIPK4), a regulator of keratinocyte differentiation and the NF-κB and Wnt/β-catenin signaling pathways, has recently emerged as a contributor to melanoma progression and therapy resistance. In this study, we investigated the interaction between melatonin signaling and RIPK4 expression in human melanoma models. We demonstrate that pharmacological concentrations of melatonin significantly reduce cell viability and proliferation in vitro, with a more pronounced effect in RIPK4-knockout (RIPK4.KO) cells. Interestingly, loss of RIPK4 led to the upregulation of melatonin receptors MT1 and MT2, although pharmacological blockade of these receptors failed to reverse melatonin-induced cytotoxicity, suggesting a predominantly receptor-independent mechanism of action. In the zebrafish xenograft model, melanoma cells pretreated with melatonin prior to injection exhibited reduced tumor growth, and the combination with RIPK4 knockout produced an additive anti-tumor effect. Our findings support a novel functional link between RIPK4 and melatonin sensitivity and highlight the potential of combining RIPK4-targeted strategies with melatonin in melanoma therapy.
Adiponectin ameliorates chronic-intermittent-hypoxia-induced insulin resistance by modulating macrophage inflammation in visceral white adipose tissue.
Weng X, Huang M, Wang W
Mol Cell Endocrinol · 2026 Aug · PMID 42055157 · Publisher ↗
BACKGROUND: Chronic intermittent hypoxia (CIH) is a key pathogenic mechanism of obstructive sleep apnea (OSA). OSA is an independent risk factor for insulin resistance (IR) in non-obese individuals, yet its underlying me...
BACKGROUND: Chronic intermittent hypoxia (CIH) is a key pathogenic mechanism of obstructive sleep apnea (OSA). OSA is an independent risk factor for insulin resistance (IR) in non-obese individuals, yet its underlying mechanisms remain unclear. Dysfunctional visceral adipose tissue (vWAT) is a central driver of insulin resistance and is closely associated with IR. Adiponectin (Ad), secreted by adipose tissue, plays a crucial role in metabolic regulation through insulin sensitization and anti-inflammatory effects. This study investigates how CIH induces IR and how Ad alleviates this effect by modulating macrophage polarization in visceral white adipose tissue (vWAT). METHODS: This study successfully established a lean murine CIH-IR model. C57BL/6J mice were divided into three groups: standard control (NC), CIH, and CIH supplemented with Ad (CIH + Ad), with 10 mice in each group. We evaluated systemic glucose homeostasis using the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) index and assessed macrophage infiltration in the white adipose tissue of both epididymides (eWAT) through immunofluorescence (IF) staining, flow cytometry, and ELISA. Additionally, we further investigated these pathways and examined key proteins in the insulin signaling pathway using RNA sequencing (RNA-seq), KEGG pathway enrichment analysis, and Western blot (WB). RESULTS: The CIH group showed a significant decrease in serum Ad levels, along with a corresponding increase in HOMA-IR, compared to the NC group. When Ad was administered to CIH mice, HOMA-IR decreased. Transcriptomic sequencing identified all the differentially expressed genes (DEGs) in eWAT among the three groups. KEGG pathway enrichment and WB analyses revealed the PI3K-AKT pathway as the key driver of functional changes in eWAT. The macrophage count and proportion in the eWAT of mice in the CIH group were significantly higher than in the NC and CIH + Ad groups, and the M1/M2 macrophage ratio was also notably increased. Levels of TNF-α, IL-6, and IL-1β in eWAT were considerably higher in the CIH group compared to both the NC and CIH + Ad groups. CONCLUSION: CIH may impair insulin signaling pathways in mouse eWAT by promoting M1 polarization of eWAT macrophages, which is likely a key mechanism of CIH-induced insulin resistance. Additionally, it is hypothesized that Ad alleviates CIH-induced insulin resistance in mice by regulating eWAT macrophage polarization and restoring insulin signaling pathways.
3D bioprinted connections in Liver‒Pancreas crosstalk: Lessons learned and future directions.
Murucci MD, Onikanni SA, da Cunha Goldstein A … +8 more , Aribigbola T, da Costa Xavier C, Olayinka OS, Dezonne RS, da Cunha Boldrini Pereira L, Bonfim DC, Miranda-Alves L, Piperni SG
Mol Cell Endocrinol · 2026 Aug · PMID 42035828 · Publisher ↗
The complexity of metabolic crosstalk between the liver and pancreas, which controls glucose and homeostasis levels, has been intriguing for models based on conventional in vitro systems. However, the 3D bioprinting path...
The complexity of metabolic crosstalk between the liver and pancreas, which controls glucose and homeostasis levels, has been intriguing for models based on conventional in vitro systems. However, the 3D bioprinting path has created an incredible platform of multicellular and spatially concerted microtissues that mimic the interaction of the pancreas. This discovery contributes important insights into metabolic organization, regenerative strategies, and disease mechanisms. Therefore, our review delves into recent advancements in 3D bioprinted crosstalk between liver and pancreas constructs, with focus on biomaterial scaffolds, engineered microenvironments, and how dynamic perfusion systems imitate signaling between hepatocytes, stromal components, and pancreatic β-cells. The relevance of nutrient flow, coculture geometry, and bioink composition to improve insulin responsiveness, lipid metabolic processes, and glucose uptake has taken the focal point, while the integration of microfluidic bioreactors and biosensing scaffolds provides real-time metabolic monitoring and testing of drugs. Persistent threats still exist in preserving tissue viability, functional connectivity, and vascularization. Future research could delve into creation of vascularized multiorgan chips and evaluate therapies, stem cell-based cell lines, and AI-backed bioprinting for customized disease modeling. Integrating bioengineering and endocrine biology in 3D bioprinting of the liver‒pancreas system could improve scientific knowledge of interorgan crosstalk in metabolic disorders.
Corrigendum to "Failure of podocalyxin suppression and HOXA10/HOXA11 activation characterizes endometrial dysfunction in hyperandrogenic PCOS" [Mol. Cell. Endocrinol 616 (2026) 112763].
Celik N, Celik O, Ulug U … +9 more , Ersahin A, Gurkan N, Gungor K, Yardim M, Dalkilic S, Tektemur A, Celik S, Gungor ND, Duran C
Mol Cell Endocrinol · 2026 Aug · PMID 42020296 · Publisher ↗
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ERα maintains the junctional function of testicular Sertoli cells by activating the PKR pathway via upregulation of c-Fos.
Ma X, Yu Z, Yang Y … +7 more , Yao Z, Wu J, Fang Y, Sun J, Mao J, Zhao H, Zhang C
Mol Cell Endocrinol · 2026 Aug · PMID 42002255 · Publisher ↗
Estrogen receptor α (ERα) is a ligand-regulated transcription factor essential for spermatogenesis and Sertoli cell junctional function. However, the molecular mechanisms underlying its regulatory role remain incompletel...
Estrogen receptor α (ERα) is a ligand-regulated transcription factor essential for spermatogenesis and Sertoli cell junctional function. However, the molecular mechanisms underlying its regulatory role remain incompletely defined. In this study, we investigated the role of ERα in maintaining Sertoli cell barrier integrity using both in vivo and in vitro models. ERα inhibition impaired spermatogenesis in vivo, as evidenced by reduced sperm viability and disrupted seminiferous tubule architecture. In both models, ERα inhibition compromised blood-testis barrier (BTB) integrity, accompanied by decreased expression of junctional proteins including Zonula occludens-1 (ZO-1), Occludin, β-Catenin, and Connexin-43 (Cx43). Mechanistically, RNA sequencing identified the Protein Kinase R (PKR) signaling pathway as a downstream effector of ERα. Functional validation further confirmed that ERα maintains Sertoli cell barrier function through activation of the PKR pathway. In addition, chromatin immunoprecipitation assays demonstrated that ERα directly binds to the c-Fos promoter to regulate its transcription, leading to increased c-Fos expression and subsequent activation of PKR signaling. These findings offer novel insights into potential therapeutic targets for testicular dysfunction.
Epigenetic heterogeneity in women with polycystic ovary syndrome.
Wang A, Liu M, Li W … +2 more , Zhu D, Tan Q
Mol Cell Endocrinol · 2026 Aug · PMID 41990965 · Publisher ↗
Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of reproductive age. As a clinically heterogeneous condition, distinct subtypes of PCOS may exist with varying clinical and biochemical features wh...
Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of reproductive age. As a clinically heterogeneous condition, distinct subtypes of PCOS may exist with varying clinical and biochemical features which impact clinical handling of PCOS. Identifying sub-clusters of PCOS women is a critical and challenging issue toward individualized treatment. Using data on the DNA methylome of PCOS cases and healthy controls, we performed an epigenome-wide association study (EWAS) on DNA methylation variability to investigate epigenetic heterogeneity of PCOS to explore the molecular basis in its clinical heterogeneity. We identified 136 CpG sites that are significantly highly variable in DNA methylation in PCOS cases (p < 1 × 10). The EWAS results were significantly enriched for biological pathways including non-alcoholic fatty liver disease, polycomb repressive complex, and Hippo signaling pathway, all have been reportedly to involve in PCOS physiopathology. Based on the identified 136 significant sites, we were able to cluster PCOS cases into two major clusters. Correlation of the clusters with observed clinical variables found four reproductive hormones i.e. estradiol, progesterone, thyroid stimulating hormone and testosterone, that optimally characterize the clustering with high statistical significance (p = 1.50 × 10). Our results showed that variability analysis of the PCOS DNA methylome can be a valuable approach for exploring the biological basis in PCOS clinical heterogeneity to promote individualized treatment and management.
Glucose deprivation impairs lipid tolerance related to mitophagy disorder in cardiomyocytes.
Huang L, Huang C, Xiao Z … +6 more , Chen X, Zhan M, Yao S, Zhu S, Chen Z, Liu L
Mol Cell Endocrinol · 2026 Aug · PMID 41962756 · Publisher ↗
Severe hypoglycemia (SH) is associated with adverse cardiac outcomes in individuals with diabetes; however, the underlying mechanisms remain poorly understood. Our previous study demonstrated that the myocardium of diabe...
Severe hypoglycemia (SH) is associated with adverse cardiac outcomes in individuals with diabetes; however, the underlying mechanisms remain poorly understood. Our previous study demonstrated that the myocardium of diabetic mice, characterized by hyperglycemia and hyperlipidemia, exhibited greater susceptibility to SH than that of non-diabetic mice. This study aimed to investigate the effects of glucose deprivation on cardiomyocytes pretreated with high glucose and lipids. The results indicated that brief exposure to high glucose and lipid levels maintained cardiomyocyte viability and enhanced PTEN-induced kinase 1 (PINK1)/Parkin-related mitophagy. However, glucose deprivation following high glucose and lipid treatment significantly increased cardiomyocyte susceptibility to injury compared with glucose deprivation after high glucose treatment alone. This was evidenced by reduced cell viability, increased apoptosis, and mitochondrial dysfunction-characterized by disrupted mitochondrial structure, depolarization, decreased adenosine triphosphate production, and impaired PINK1/Parkin-related mitophagy in the cells. These adverse effects were reversed by treatment with the mitophagy activator urolithin A. Our findings suggest that glucose plays a critical role in maintaining lipid tolerance via mitophagy in cardiomyocytes, a mechanism that may contribute to the pathogenesis of SH-induced myocardial injury.
PDK1 downregulation impairs decidualization via dysregulated glycolysis: Potential relevance to preeclampsia.
Liu Y, Li H, Zhang L … +5 more , Tong J, Liu H, Yan X, Liu L, Zhang C
Mol Cell Endocrinol · 2026 Aug · PMID 41951203 · Publisher ↗
Preeclampsia (PE) is a pregnancy-specific syndrome affecting over 8 million mother-infant pairs annually; while most prior studies on PE pathogenesis have focused on the placenta, decidualization is fundamental to placen...
Preeclampsia (PE) is a pregnancy-specific syndrome affecting over 8 million mother-infant pairs annually; while most prior studies on PE pathogenesis have focused on the placenta, decidualization is fundamental to placentation and subsequent pregnancy progression. Pyruvate dehydrogenase kinase-1 (PDK1) is a key regulator of metabolic switching, as it promotes glycolysis and inhibits oxidative phosphorylation. Although PDK1 is aberrantly upregulated in various tumors, its role in PE remains unclear. In this study, we first observed that PDK1 expression in decidual tissues was significantly lower in patients with severe PE than in normal pregnant women. In vitro, PDK1 expression increased significantly during the decidualization of human endometrial stromal cells, accompanied by upregulated mRNA levels of aerobic glycolysis-related genes (LDHA and MCT4) and downregulated expression of the oxidative phosphorylation enzyme IDH2. Moreover, PDK1 knockdown impaired decidualization, significantly reduced LDHA and MCT4 expression, increased IDH2 levels, suppressed glucose uptake and lactate production, and inhibited trophoblast invasion. In vivo experiments in mice further confirmed that PDK1 expression increases with decidual progression during both normal pregnancy and pseudopregnancy, which is paralleled by enhanced glycolysis and reduced oxidative phosphorylation. Collectively, these findings indicate that PDK1 plays a critical role in decidualization through promoting glycolysis and inhibiting oxidative phosphorylation, with aberrant PDK1 expression potentially impairing decidualization and being associated with PE pathogenesis.
Concept and connotation of the geroprotective and anti-aging effects of metformin: From AMPK activation to SASP suppression.
Aedh AI, Al-Kuraishy HM, Shokr MM … +2 more , Alruwaili M, El-Saber Batiha G
Mol Cell Endocrinol · 2026 Aug · PMID 41942023 · Publisher ↗
Biological aging is the risk factor underlying most of the chronic diseases of late life, such as cardiovascular disease, cancer, and neurodegeneration. Despite more than fifteen years of intensive research and the evalu...
Biological aging is the risk factor underlying most of the chronic diseases of late life, such as cardiovascular disease, cancer, and neurodegeneration. Despite more than fifteen years of intensive research and the evaluation of hundreds of candidate compounds, no pharmacological therapy has yet been approved to target aging itself, leaving clinical medicine without an intervention that addresses the fundamental driver of multi-morbidity in older populations. It has been shown that the anti-diabetic metformin reduces mortality and the incidence of several age-related diseases in both diabetic and non-diabetic populations, independent of glycemic control. At standard therapeutic plasma concentrations achieved in aged human tissues, metformin engages multiple interconnected hallmarks of aging, such as activation of AMP-activated protein kinase (AMPK), inhibition of mechanistic target of rapamycin (mTOR) signaling, restoration of autophagy, modulation of other signaling pathways, improvement of mitochondrial function, and attenuation of senescence-associated inflammatory signaling. Large observational cohorts and meta-analyses further demonstrate that metformin use is associated with mechanistic plausibility, epidemiological consistency, and an unparalleled long-term safety record. Conversely, metformin may adversely affect the aging process when administered in aged animals, suggesting a controversial role of metformin effect on aging process. Nevertheless, the exact cellular and molecular mechanisms of the anti-aging role of metformin are not fully elucidated. Thus, this review integrates preclinical, epidemiological, and randomized clinical evidence supporting the role of metformin in aging to discuss and explain the possible anti-aging role of metformin.
Histone deacetylases inhibitor Chidamide mitigates inflammation and insulin resistance by targeting VDR in skeletal muscle cells.
Zhang L, Zhang M, Zhu M … +4 more , Luo X, Cui L, Zhao Y, Zhao JM
Mol Cell Endocrinol · 2026 Aug · PMID 41942022 · Publisher ↗
The pathogenesis of Type 2 diabetes mellitus (T2DM) is heavily driven by exacerbated insulin resistance and inflammation in skeletal muscle, a major site for insulin-stimulated glucose uptake. Therefore, targeting inflam...
The pathogenesis of Type 2 diabetes mellitus (T2DM) is heavily driven by exacerbated insulin resistance and inflammation in skeletal muscle, a major site for insulin-stimulated glucose uptake. Therefore, targeting inflammation and insulin resistance within this tissue represents an effective therapeutic strategy for T2DM. While histone deacetylase inhibitors (HDACi) exhibit therapeutic potential for metabolic diseases, the specific impact of the novel HDACi, Chidamide, on regulating skeletal muscle insulin resistance remains to be elucidated. Here, we provide in vitro evidence that Chidamide mitigates skeletal muscle inflammation and insulin resistance in a palmitic acid (PA)-induced C2C12 cell model. We demonstrate that Chidamide alleviates inflammation and activates the Akt/GSK3β/AS160-mediated insulin signaling thereby promoting cell-surface localization of GLUT4 and glucose uptake. Mechanistically, PA downregulates the expression of the vitamin D receptor (VDR), contributing to the inflammatory response and impairing Akt/GSK3β/AS160-mediated insulin signaling, which ultimately inhibited GLUT4-mediated glucose uptake. Chidamide effectively alleviates these effects by upregulating VDR transcription, potentially through the augmentation of histone H3 acetylation, thereby restoring insulin sensitivity and increasing GLUT4-mediated glucose uptake. In conclusion, our findings provide a proof-of-concept for the potential utility of Chidamide as a therapeutic strategy to enhance skeletal muscle insulin sensitivity.
Etomidate relieves oxaliplatin-induced neuropathic pain by regulating AMPK/Nrf2/HO-1 axis.
Chen K, Lin Y, Han X … +3 more , Zhao L, Wang J, Li Y
Mol Cell Endocrinol · 2026 Apr · PMID 41936904 · Publisher ↗
BACKGROUND: Etomidate (Eto) is widely employed in clinical anesthesia induction. Whereas, the function of Eto in neuropathic pain caused by anticancer chemotherapeutic drug remains indistinct. Hereof, the research attemp...
BACKGROUND: Etomidate (Eto) is widely employed in clinical anesthesia induction. Whereas, the function of Eto in neuropathic pain caused by anticancer chemotherapeutic drug remains indistinct. Hereof, the research attempted to unveil the regulatory mechanisms of Eto in oxaliplatin (OXA) elicited neuropathic pain. MATERIAL AND METHODS: The mice model was established by OXA induction and administrated by Eto along with the concentrations of 1.5, 3 and 6 mg/kg. The nociceptive behaviors such as paw withdrawal threshold (PWT), flinches, paw withdrawal latency (PWL) and latency were analyzed. By executing HE staining, RT-qPCR, western blot and the corresponding kits, the influences of Eto in inflammatory response and oxidative stress response in OXA model were explored. AMPK/Nrf2/HO-1 pathways were studied to uncover the potential mechanism. After creation of C6 cells model, the effects of Eto in neuropathic pain were further investigated in vitro. RESULTS: Eto significantly relieved OXA-irritated nociceptive behaviors via elevating the values of PWT and PWL, declining the number of spontaneous flinches, meanwhile restoring latency to fall. Moreover, Eto triggered a robust anti-inflammatory response, which lowered inflammatory scores and suppressed GFAP, IL-1β, TNF-α and NLRP3 expression. Additionally, Eto obviously enhanced SOD and GSH levels, but reduced MDA and COX2 levels, thereby mitigating OXA-induced oxidative stress response. Mechanism study discovered that activation of AMPK/Nrf2/HO-1 pathways participated in regulating the neuroprotective function of Eto in inflammatory response and oxidative stress response in OXA-treated mice and in C6 cells model. CONCLUSIONS: The research announced that Eto improved OXA-induced neuropathic pain by regulating AMPK/Nrf2/HO-1 pathway.
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