Epigenetics-targeted drugs: current paradigms and future challenges

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Ноя. 26, 2024

Epigenetics governs a chromatin state regulatory system through five key mechanisms: DNA modification, histone RNA remodeling, and non-coding regulation. These mechanisms their associated enzymes convey genetic information independently of base sequences, playing essential roles in organismal development homeostasis. Conversely, disruptions epigenetic landscapes critically influence the pathogenesis various human diseases. This understanding has laid robust theoretical groundwork for developing drugs that target epigenetics-modifying pathological conditions. Over past two decades, growing array small molecule targeting such as methyltransferase, deacetylase, isocitrate dehydrogenase, enhancer zeste homolog 2, have been thoroughly investigated implemented therapeutic options, particularly oncology. Additionally, numerous epigenetics-targeted are undergoing clinical trials, offering promising prospects benefits. review delineates epigenetics physiological contexts underscores pioneering studies on discovery implementation drugs. include inhibitors, agonists, degraders, multitarget agents, aiming to identify practical challenges avenues future research. Ultimately, this aims deepen epigenetics-oriented strategies further application settings.

Язык: Английский

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Targeting sirtuins for cancer therapy: epigenetics modifications and beyond

Theranostics, Год журнала: 2024, Номер 14(17), С. 6726 - 6767

Опубликована: Янв. 1, 2024

Sirtuins (SIRTs) are well-known as nicotinic adenine dinucleotide

Язык: Английский

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Emerging roles of mitochondrial sirtuin SIRT5 in succinylation modification and cancer development

Frontiers in Immunology, Год журнала: 2025, Номер 16

Опубликована: Янв. 29, 2025

Succinylation represents an emerging class of post-translational modifications (PTMs), characterized by the enzymatic or non-enzymatic transfer a negatively charged four-carbon succinyl group to ϵ-amino lysine residues, mediated succinyl-coenzyme A. Recent studies have highlighted involvement succinylation in various diseases, particularly cancer progression. Sirtuin 5 (SIRT5), member sirtuin family, has been extensively studied for its robust desuccinylase activity, alongside deacetylase function. To date, only limited number SIRT5 substrates identified. These mediate diverse physiological processes such as glucose oxidation, fatty acid ammonia detoxification, reactive oxygen species scavenging, anti-apoptosis, and inflammatory responses. The regulation these activities can occur through either same activity acting on different distinct targeting substrate. Aberrant expression closely linked tumorigenesis disease progression; however, role remains controversial. exhibits dual functionalities: it promote tumor proliferation, metastasis, drug resistance, metabolic reprogramming, thereby oncogene; conversely, also inhibit cell growth induce apoptosis, functioning suppressor gene. This review aims provide comprehensive overview current research status SIRT5. We discuss structural characteristics regulatory mechanisms, compare functions with other family members, elucidate mechanisms regulating activity. Specifically, we focus modification progression, highlighting how desuccinylation modulates development delineating underlying involved.

Язык: Английский

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Enhanced SIRT3 expression restores mitochondrial quality control mechanism to reverse osteogenic impairment in type 2 diabetes mellitus

Bone Research, Год журнала: 2025, Номер 13(1)

Опубликована: Март 3, 2025

Abstract Osteoporosis represents a prevalent and debilitating comorbidity in patients diagnosed with type 2 diabetes mellitus (T2DM), which is characterized by suppressed osteoblast function disrupted bone microarchitecture. In this study, we utilized male C57BL/6 J mice to investigate the role of SIRT3 T2DM. Decreased expression impaired mitochondrial quality control mechanism are observed both vitro vivo models Mechanistically, suppression results hyperacetylation FOXO3, hindering activation PINK1/PRKN mediated mitophagy pathway resulting accumulation dysfunctional mitochondria. Genetical overexpression or pharmacological restores deacetylation status thus facilitating ameliorating osteogenic impairment Collectively, our findings highlight fundamental regulatory control, crucial for maintaining homeostasis These insights not only enhance understanding molecular mechanisms underlying diabetic osteoporosis but also identify as promising therapeutic target osteoporosis.

Язык: Английский

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SETDB1 recruits CBX3 to regulate the SIRT4/PTEN axis, inhibiting autophagy and promoting ischemia–reperfusion‐induced kidney injury

The FASEB Journal, Год журнала: 2025, Номер 39(7)

Опубликована: Апрель 8, 2025

Abstract Ischemia–reperfusion (I/R) injury is a significant factor in the development of acute kidney (AKI), particularly clinical scenarios, such as transplantation, cardiac surgery, and severe hypotension. Autophagy, critical process that eliminates damaged cellular components, has been shown to mitigate I/R by reducing oxidative stress enhancing cell survival. However, when autophagy disrupted, it can exacerbate damage. Elucidating role essential for uncovering molecular mechanisms driving AKI could facilitate autophagy‐based therapies. Protein expression levels were analyzed through western blot, immunohistochemistry (IHC), immunofluorescence (IF) staining techniques. Interactions between SIRT4, SETDB1, CBX3 explored using chromatin immunoprecipitation (ChIP), sequential ChIP (ChIP‐reChIP), co‐immunoprecipitation (Co‐IP) assays. The association SIRT4 PTEN was also examined via Co‐IP. Transmission electron microscopy (TEM) employed visualize autophagosomes. Furthermore, an vivo rat model developed validation findings. Sirtuin 4 (SIRT4) reduced, impaired during injury. Moreover, interacted with phosphatase tensin homolog (PTEN) regulate its expression. SET domain bifurcated histone lysine methyltransferase 1 (SETDB1) mediated H3 9 trimethylation (H3K9me3) modifications recruited chromobox protein 3 (CBX3) promoter, leading repression proximal tubular cells. Importantly, SETDB1 knockdown upregulated decreased expression, promoted autophagy, protected rats against vivo. recruits SIRT4/PTEN axis, inhibiting promoting I/R‐induced These results suggest targeting SETDB1‐SIRT4 axis offer novel therapeutic strategy renal damage AKI.

Язык: Английский

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Unraveling Small Molecule-Mediated Sirtuin 3 Activation at a Distinct Binding Site for Cardioprotective Therapies

ACS Central Science, Год журнала: 2025, Номер unknown

Опубликована: Апрель 13, 2025

Язык: Английский

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Single-Sample Networks Reveal Intra-Cytoband Co-Expression Hotspots in Breast Cancer Subtypes

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(22), С. 12163 - 12163

Опубликована: Ноя. 13, 2024

Breast cancer is a heterogeneous disease comprising various subtypes with distinct molecular characteristics, clinical outcomes, and therapeutic responses. This heterogeneity evidences significant challenges for diagnosis, prognosis, treatment. Traditional genomic co-expression network analyses often overlook individual-specific interactions critical personalized medicine. In this study, we employed single-sample gene analysis to investigate the structural functional alterations across breast (Luminal A, Luminal B, Her2-enriched, Basal-like) compared them normal tissue. We utilized RNA-Seq expression data infer networks. The LIONESS algorithm allowed us construct individual networks each patient, capturing unique patterns. focused on top 10,000 ensure consistency robustness in our analysis. Network metrics were calculated characterize topological properties of both aggregated Our findings reveal fragmentation subtypes, marked by change from interchromosomal (TRANS) intrachromosomal (CIS) interactions. transition indicates disrupted long-range communication, leading localized regulation increased instability. Single-sample confirmed that these patterns are consistent at level, highlighting cancer. Despite pronounced alterations, proportion CIS did not significantly correlate patient survival outcomes suggesting limited prognostic value. Furthermore, identified high-degree genes cytobands specific subtype, providing insights into subtype-specific regulatory potential targets. These play pivotal roles oncogenic processes may represent important keys targeted interventions. application proves be powerful tool uncovering

Язык: Английский

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Molecular Sentinels: Unveiling the Role of Sirtuins in Prostate Cancer Progression

International Journal of Molecular Sciences, Год журнала: 2024, Номер 26(1), С. 183 - 183

Опубликована: Дек. 28, 2024

Prostate cancer (PCa) remains a critical global health challenge, with high mortality rates and significant heterogeneity, particularly in advanced stages. While early-stage PCa is often manageable conventional treatments, metastatic notoriously resistant, highlighting an urgent need for precise biomarkers innovative therapeutic strategies. This review focuses on the dualistic roles of sirtuins, family NAD+-dependent histone deacetylases, dissecting their unique contributions to tumor suppression or progression depending cellular context. It reveals multifaceted impact hallmark processes, including sustaining proliferative signaling, evading growth suppressors, activating invasion metastasis, resisting cell death, inducing angiogenesis, enabling replicative immortality. SIRT1, example, fosters chemoresistance castration-resistant prostate through metabolic reprogramming, immune modulation, androgen receptor enhanced DNA repair. SIRT3 SIRT4 suppress oncogenic pathways by regulating metabolism, while SIRT2 SIRT6 influence aggressiveness sensitivity, promoting potential. Notably, SIRT5 oscillates between tumor-suppressive key enzymes; whereas, SIRT7 drives proliferation stress adaptation its chromatin nucleolar regulatory functions. Furthermore, we provide comprehensive summary individual potential as exploring implications. By examining each these specific mechanisms which sirtuins PCa, this underscores sirtuin modulation address gaps managing PCa. Understanding sirtuins’ effects could redefine approaches, precision strategies that enhance treatment efficacy improve outcomes patients aggressive disease.

Язык: Английский

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Design, synthesis and biological evaluation of new SIRT3 activators for the treatment of triple-negative breast cancer

Bioorganic & Medicinal Chemistry, Год журнала: 2024, Номер 118, С. 118040 - 118040

Опубликована: Дек. 11, 2024

Язык: Английский

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