International Journal of Biological Sciences最新文献

Liver diseases present a formidable global health challenge and rank among the leading causes of morbidity and premature mortality worldwide. Silent information regulator 1 (SIRT1), a nicotinamide adenine dinucleotide (NAD⁺)-dependent histone deacetylase, has emerged as a crucial regulator of various pathophysiological processes, including metabolic homeostasis, inflammatory responses and apoptosis. This evolutionarily conserved enzyme exhibits a disease‑specific expression profile and is subject to tightly regulated mechanisms in diverse liver diseases. In recent years, accumulating evidence has highlighted the critical involvement of SIRT1 dysregulation in the pathogenesis of various liver diseases. In this review, we provide a comprehensive overview of the roles of SIRT1 in multiple liver diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-associated liver disease (ALD), liver fibrosis, and hepatocellular carcinoma (HCC). We further explore the underlying regulatory mechanisms, aiming to establish a rigorous framework to facilitate the clinical translation of SIRT1-targeted therapeutic strategies.

The proteasome plays a pivotal role in proteostasis and is deeply involved in various cellular processes. Currently, three proteasome inhibitors have been used for clinical therapies of liquid cancers with favorable efficacy, however they fail to achieve ideal efficiency in clinical trials for solid cancers without a clear clue. Recent studies have unveiled that beyond its canonical role in ubiquitin-mediated protein degradation, the proteasome also elicits a multifaceted influence on T cell fate, steering it through antigen processing, metabolic reprogramming, and the prevention of exhaustion. The proteasome inhibitors may affect tumor progression through their critical role in modulating T cell-mediated antitumor immunity, an understanding of which may solve the mystery underlying the poor efficacy of the proteasome inhibitors for solid cancers and unlock novel strategies for precision immunotherapy. This review will summarize the current knowledge of how proteasome activity weaves its threads through thymic selection, T cell aging, activation, differentiation, and immune evasion. Moreover, we will explore how cutting-edge technologies-CRISPR editing, single-cell proteomics, and AI-driven drug design can expand the application of the proteasome inhibitors in the treatment of cancer and autoimmune diseases.

Impaired clearance of all-trans-retinal (atRAL) due to visual cycle dysfunction contributes to photoreceptor atrophy, a key pathological hallmark of Stargardt disease type 1 (STGD1) and dry age-related macular degeneration (AMD). Prior studies have shown that light-induced atRAL accumulation promotes ferroptosis and activates gasdermin E (GSDME) in retinal photoreceptors of Abca4^-/-Rdh8^-/- mice, a model for STGD1 and dry AMD that exhibits visual cycle disorders. However, the role of GSDME in photoreceptor ferroptosis remains unclear. In this study, we revealed that GSDME activation by atRAL triggered photoreceptor ferroptosis and retinal atrophy via mitochondrial damage and oxidative stress. Knocking out GSDME significantly attenuated light-induced photoreceptor ferroptosis and retinal degeneration in Abca4^-/-Rdh8^-/- mice. Moreover, deleting the Gsdme gene in photoreceptor cells prevented atRAL-induced ferroptosis by inhibiting mitochondrial reactive oxygen species (mitoROS) production, iron overload, and lipid peroxidation. Notably, treatment with the mitoROS scavenger MitoTEMPO mitigated ferroptosis in atRAL-loaded photoreceptor cells and dramatically relieved photoreceptor ferroptosis and retinal degeneration in light-exposed Abca4^-/-Rdh8^-/- mice. We found that both GSDME elimination and MitoTEMPO treatment repressed atRAL-induced photoreceptor ferroptosis and retinal atrophy by inactivating the mitoROS-induced oxidative stress. In conclusion, GSDME-mediated photoreceptor ferroptosis is crucial for inducing structural and functional damage of the retina in retinopathies caused by atRAL accumulation, thereby providing new therapeutic insights for the prevention and treatment of STGD1 and dry AMD.

Liver fibrosis has emerged as the primary determinant of outcomes in metabolic dysfunction-associated steatohepatitis (MASH). Quiescent hepatic stellate cells (HSCs) differentiate into activated HSCs or myofibroblasts, which drives liver fibrosis and contribute to the progressive loss of hepatic function. MASH with progressive fibrosis lacks effective therapies due to incomplete understanding of HSCs regulation. Here, we identify growth differentiation factor 10 (GDF10) as a master regulator of HSCs quiescence that ameliorates fibrosis through shifting HSC functions to restore HSC balance of transcriptional and metabolic reprogramming. Single-cell RNA sequencing revealed HSC-specific Gdf10 expression inversely correlated with fibrotic activation. In murine models of diet-induced MASH and CCl4-induced fibrosis, AAV-mediated Gdf10 overexpression reduced collagen deposition, serum ALT/AST, and fibrogenic gene expression without perturbing glucose or lipid metabolism. Mechanistically, GDF10 competitively bound TGF-β receptor 2 (TβR2), inhibiting SMAD2/3 phosphorylation and nuclear translocation, ultimately suppressing TGFβ1-driven extracellular matrix production, and reversing the activated HSCs phenotype and their hypermetabolic states. Leveraging this pathway, we developed liver-targeted lipid nanoparticles (LNPs) encapsulating mGdf10 mRNA, which selectively delivered Gdf10 to HSCs, reversed fibrosis in multiple animal models. Clinically, GDF10 expression correlated with fibrosis severity in human cirrhotic livers. Our findings establish GDF10 as a dual-function modulator of TGF-β signaling and HSC metabolism, offering a targeted therapeutic strategy for liver fibrosis.

Despite significant progress in breast cancer treatment, more effective methods for its clinical management are still needed. Our data identified that fat mass and obesity-associated protein (FTO), an N ⁶-methyladenosine (m⁶A) demethylase, is highly expressed in breast cancer and promotes tumorigenesis. Inhibiting FTO can suppress the proliferation and metastasis of breast cancer, while its efficacy needs to be further improved. Through screening with 27 clinically approved targeted therapy drugs, we discovered that ibrutinib, a BTK inhibitor, shows the highest cell death rate and lowest combination index (CI). This combination demonstrates a potent synergistic effect in the malignancy of breast cancer and its lung metastasis. RNA-seq showed that the oncogenic pathways regulated by c-Myc and E2F1 were among the most down-regulated in cells treated with FTO inhibitor and ibrutinib. Furthermore, this combination decreases the expression of both c-Myc and E2F1. Contrarily, overexpressing c-Myc and E2F1 counteracts this antitumor effectiveness. Mechanistically, this combination inhibits c-Myc and E2F1 expression by increasing m⁶A modification of their mRNAs and reducing their mRNA stability. In mouse models of cancer, combining FTO knockdown with ibrutinib markedly suppressed tumor growth, decreased metastasis, and improved survival. Collectively, the combined inhibition of FTO and BTK exhibited substantial synergistic anticancer effects in breast cancer. Our findings advocate for the evaluation of this combination in clinical trials.

Pancreatic neuroendocrine tumors (pNETs) represent a diverse category of neoplasms originating from pancreatic neuroendocrine cells. Although these tumors generally exhibit a relatively indolent nature, they often metastasize early in their course, significantly affecting patient outcomes. Sulfatinib (SULF) is associated with considerable toxicity and resistance challenges, leading to many patients failing to achieve long-term disease management. In contrast, Kaempferol (KMP), a naturally occurring phytochemical, has shown considerable promise in anti-tumor treatments. Our study revealed that the combination of SULF and low-dose KMP enhances the sensitivity of pNET cells to SULF. Moreover, this combination demonstrated a synergistic effect on angiogenesis inhibition, observed in both in vitro and in vivo environments. Additionally, we confirmed this synergistic anti-tumor effect using a subcutaneous tumor model of pNETs. Transcriptome sequencing identified CALCA as a key molecule in the synergistic inhibition of pNETs proliferation by SULF and KMP. In summary, our findings provide novel insights into combination therapy for pNETs while elucidating the mechanistic role of CALCA in the modulation of angiogenesis. This research establishes a foundation for the development of vascular-targeted combination therapeutic strategies for the treatment of pNETs.

The vascular system plays a crucial role in maintaining homeostasis, ensuring the supply of oxygen and nutrients to tissues, while facilitating the removal of metabolic waste. Additionally, it contributes to immune defense, temperature regulation, and the transport of hormones and signaling molecules. Vascular anomaly (VA) arises due to developmental abnormalities or functional defects in the vessels. This review describes venous malformations (VM), a rare disorder predominantly caused by somatic mutations. Advances in recent research have substantially improved our understanding of the molecular mechanisms underlying these malformations, largely through the identification of their genetic origins and the study of animal models and endothelial cells derived from patients. Most of the somatic mutations associated with venous malformations affect genes within oncogenic growth factor signaling pathways, making it possible to repurpose certain cancer therapies to treat these VAs. This article summarizes the key molecular findings and explores emerging therapeutic strategies aimed at novel targets.

Biliary and pancreatic malignant tumors refer to biliary tract carcinoma (BTC) and pancreatic cancer (PC), among which BTC mainly includes cholangiocarcinoma (CCA) and gallbladder cancer (GBC), and their prognosis is poor because of the lack of effective early diagnostic methods. Although surgical resection is the preferred method for a cure, treatment options are limited for patients with advanced tumors. Therefore, the exploration of other new treatment methods is urgently needed. Currently, metabolic reprogramming is a key mechanism in the process of tumor development and progression and is closely related to cancer cell proliferation, metastasis and drug resistance. As an indispensable part of metabolic reprogramming in tumor cells, amino acid (AA) metabolic reprogramming provides an energy source for tumor cells and participates in regulating the tumor microenvironment (TME). Moreover, as important intrinsic myeloid cells, macrophages play indispensable physiological roles in malignant tumor progression. In the TME, tumor cells can not only induce peripheral immune tolerance by releasing extracellular signals but also compete with tumor-associated macrophages (TAMs) for AAs and release the resulting downstream metabolites into the TME, directly targeting and damaging immune cells and influencing macrophage polarization. Consequently, a more profound understanding of the function of AA metabolic reprogramming in biliopancreatic malignancies and their associated macrophage polarization holds the potential to facilitate the development of effective strategies for early diagnosis, prognostic assessment and targeted therapy in patients with biliopancreatic malignancies. In this paper, we review the impact of AA metabolic reprogramming on the occurrence and development of biliary and pancreatic malignant tumors, summarize the relevant mechanisms of AA metabolic reprogramming on the polarization of TAMs, and provide new therapeutic targets for AA metabolic therapies and immunotherapies for biliary and pancreatic malignant tumors.

Metabolic reprogramming is a hallmark of cancer, enabling tumor cells to sustain growth, evade immune surveillance, and resist therapy. Urological tumors, including prostate, bladder, and renal cancers, exhibit distinct metabolic phenotypes driven by their unique tumor microenvironments and oncogenic pathways. This review explores the emerging landscape of tumor metabolism in urological cancers, highlighting key metabolic pathways such as glycolysis, lipid metabolism, amino acid metabolism, and redox balance. We discuss how these pathways are intricately linked to tumor progression, therapeutic resistance, and immune evasion. Furthermore, we examine novel therapeutic strategies targeting metabolic vulnerabilities, including metabolic enzyme inhibitors, synthetic lethality approaches, and metabolic modulation to enhance immunotherapy. By integrating advances in multi-omics technologies and preclinical models, we propose a framework for translating metabolic research into clinical applications. This review aims to provide a comprehensive overview of metabolic reprogramming in urological tumors and to identify potential metabolic targets for innovative therapies.

Excessive Hedgehog (Hh) signaling activity contributes to fibrosis in multiple organs. However, its role in pancreatic stellate cell (PSC) activation and fibrosis development during chronic pancreatitis (CP) remains elusive. We show that GLI2 is one of the top-ranked effectors in the pancreas of CP patients and is highly expressed in activated PSCs. PSC-specific deletion of Gli2, but not Smo, significantly reduces fibrosis and the severity of the mouse CP, indicating that GLI2 in PSCs can be driven by non-canonical fashion during CP. In culture-activated primary PSCs, early nuclear translocation and increased GLI2 expression are observed promptly following in vitro culture. Whereas GLI2 inhibition reduces PSC activation, SMO inhibition dose not consistently affect changes in GLI2 levels or PSC activation. TGF-β1 promotes GLI2 activation and expression, while these processes and resultant PSC activation are reversed by TGF-β1/SMAD3 inhibition. Altogether, these findings demonstrate the activation of the non-canonical Hh pathway in PSCs during CP and highlight that GLI2 represents a promising therapeutic target for CP.