Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): from bench to bedside

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

Опубликована: Янв. 8, 2024

Proprotein convertase subtilisin/kexin type 9 (PCSK9) has evolved as a pivotal enzyme in lipid metabolism and revolutionary therapeutic target for hypercholesterolemia its related cardiovascular diseases (CVD). This comprehensive review delineates the intricate roles wide-ranging implications of PCSK9, extending beyond CVD to emphasize significance diverse physiological pathological states, including liver diseases, infectious autoimmune disorders, notably, cancer. Our exploration offers insights into interaction between PCSK9 low-density lipoprotein receptors (LDLRs), elucidating substantial impact on cholesterol homeostasis health. It also details evolution PCSK9-targeted therapies, translating foundational bench discoveries bedside applications optimized patient care. The advent clinical approval innovative inhibitory therapies (PCSK9-iTs), three monoclonal antibodies (Evolocumab, Alirocumab, Tafolecimab) one small interfering RNA (siRNA, Inclisiran), have marked significant breakthrough medicine. These demonstrated unparalleled efficacy mitigating hypercholesterolemia, reducing risks, showcased profound value applications, offering novel avenues promising future personalized medicine disorders. Furthermore, emerging research, inclusive our findings, unveils PCSK9's potential role indicator cancer prognosis prospective application transformative treatment. highlights aberrant expression various forms, association with prognosis, crucial carcinogenesis immunity. In conclusion, this synthesized integrates existing knowledge providing holistic perspective reshaping paradigms across emphasizes effect PCSK9-iT, underscoring advancing landscape biomedical research capabilities heralding new eras

Язык: Английский

---

The Causal Relationship between PCSK9 Inhibitors and Malignant Tumors: A Mendelian Randomization Study Based on Drug Targeting

Genes, Год журнала: 2024, Номер 15(1), С. 132 - 132

Опубликована: Янв. 21, 2024

Objective: This study explores the potential causal association between proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors and tumor development using Mendelian randomization (MR) based on drug targets. Methods: Instrumental variables within ±100 kb of PCSK9 gene locus, impacting low-density lipoprotein cholesterol (LDL-C), were utilized for MR analysis. Coronary heart disease (CHD) served as a positive control to validate relationship various cancers. We employed reverse address causation concerns. Data from controls tumors sourced OpenGWAS. Results: analysis suggested negative both breast lung cancers (95%CIBreast cancer 0.81~0.99, p = 2.25 × 10−2; 95%CILung 0.65~0.94, 2.55 10−3). In contrast, link was observed with gastric, hepatic, oral pharyngeal cervical intraepithelial neoplasia (95%CIGastric 1.14~1.75, 1.88 95%CIHepatic 1.46~2.53, 1.16 95%CIOral cavity 4.49~6.33, 3.36 10−4; 95%CICarcinoma in situ cervix uteri 4.56~7.12, 6.91 10−3), without heterogeneity or pleiotropy (p > 0.05). Sensitivity analyses confirmed these findings. The results targets no bladder cancer, thyroid pancreatic colorectal malignant neoplasms kidney (except renal pelvis tumors), brain, esophagus Reverse helped mitigate effects. Conclusions: indicates divergent certain While negatively associated cancers, cavity, carcinoma situ. No links found bladder, thyroid, pancreatic, colorectal, kidney, esophageal

Язык: Английский

---

Tetrahydroberberine alleviates high-fat diet-induced hyperlipidemia in mice via augmenting lipoprotein assembly-induced clearance of low-density lipoprotein and intermediate-density lipoprotein

European Journal of Pharmacology, Год журнала: 2024, Номер 968, С. 176433 - 176433

Опубликована: Фев. 16, 2024

Язык: Английский

---

Atherosclerosis, Diabetes Mellitus, and Cancer: Common Epidemiology, Shared Mechanisms, and Future Management

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(14), С. 11786 - 11786

Опубликована: Июль 22, 2023

The involvement of cardiovascular disease in cancer onset and development represents a contemporary interest basic science. It has been recognized, from the most recent research, that metabolic syndrome-related conditions, ranging atherosclerosis to diabetes, elicit many pathways regulating lipid metabolism signaling are also linked same framework multiple potential mechanisms for inducing cancer. Otherwise, dyslipidemia endothelial cell dysfunction may present common or even interdependent changes, similar oncogenic molecules elevated forms However, whether atherosclerotic provides signals promote pre-clinical proliferation malignant cells is an issue requires further understanding, though more questions presented with every answer. Here, we highlight molecular point causal link between glucose homeostasis knowledge these breakthrough pave way application new therapeutic targets implementing interventions clinical practice.

Язык: Английский

---

Arenobufagin modulation of PCSK9-mediated cholesterol metabolism induces tumor-associated macrophages polarisation to inhibit hepatocellular carcinoma progression

Phytomedicine, Год журнала: 2024, Номер 128, С. 155532 - 155532

Опубликована: Март 13, 2024

Язык: Английский

---

The multifaceted role of PCSK9 in cancer pathogenesis, tumor immunity, and immunotherapy

Medical Oncology, Год журнала: 2024, Номер 41(8)

Опубликована: Июль 15, 2024

Язык: Английский

---

Why make it if you can take it: review on extracellular cholesterol uptake and its importance in breast and ovarian cancers

Journal of Experimental & Clinical Cancer Research, Год журнала: 2024, Номер 43(1)

Опубликована: Сен. 6, 2024

Язык: Английский

---

Inhibition of PCSK9: a promising enhancer for anti-PD-1/PD-L1 immunotherapy

Research, Год журнала: 2024, Номер 7

Опубликована: Янв. 1, 2024

Immune checkpoint therapy, such as programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) blockade, has achieved remarkable results in treating various tumors. However, most cancer patients show a low response rate to PD-1/PD-L1 especially those with microsatellite stable/mismatch repair-proficient colorectal subtypes, which indicates an urgent need for new approaches augment the efficacy of blockade. Cholesterol metabolism, involves generating multifunctional metabolites and essential membrane components, is also instrumental tumor development. In recent years, inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9), serine proteinase that regulates cholesterol been demonstrated be method enhancing antitumor effect blockade some extent. Mechanistically, PCSK9 inhibition can maintain recycling major histocompatibility class I, promote low-density lipoprotein receptor-mediated T-cell receptor signaling, modulate microenvironment (TME) by affecting infiltration exclusion immune cells. These mechanisms increase quantity enhance antineoplastic cytotoxic T lymphocyte, main functional cells involved anti-PD-1/PD-L1 immunotherapy, TME. Therefore, combining therapy immunotherapy may provide novel option improving effects constitute promising research direction. This review concentrates on relationship between systematically discusses how potentiates treatment, highlights directions this field.

Язык: Английский

---

Cardiovascular Disease and Cancer: A Dangerous Liaison

Arteriosclerosis Thrombosis and Vascular Biology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 9, 2025

The field of cardio-oncology has traditionally focused on the impact cancer and its therapies cardiovascular health. Mounting clinical preclinical evidence, however, indicates that reverse may also be true: disease can itself influence tumor growth metastasis. Numerous epidemiological studies have reported individuals with prevalent an increased incidence cancer. In parallel, using mouse models myocardial infarction, heart failure, cardiac remodeling support notion disorders accelerate solid tumors metastases. These findings ushered in a new burgeoning termed investigates cause pathophysiology emergence progression. Recent begun to illuminate mechanisms driving this relationship, including shared risk factors, reprogramming immune responses, changes gene expression, release factors result selective advantages for cells or their local milieu, thus exacerbating pathology. Here, we review evidence supporting relationship between cancer, mechanistic pathways enabling connection, implications these patient care.

Язык: Английский

---

The role of lipids and lipids lowering drugs in human papillomavirus (HPV) and HPV-associated cancers

Infectious Agents and Cancer, Год журнала: 2025, Номер 20(1)

Опубликована: Янв. 28, 2025

Both women and men are now confronted with the grave threat of cancers caused by human papillomavirus (HPV). It is estimated that 80% may encounter HPV over their lives. In preponderance cases involving anal, head neck, oral, oropharyngeal, penile, vaginal, vulvar, cervical malignancies, high-risk (HR-HPV) causative agent. 2019, believed to have been cause 620,000 new cancer in 70,000 worldwide. The bulk 530,000 (~ 270,000 fatalities) infection (86% cases, 88% deaths) happen poor nations each year. Lipid metabolism crucial development related HPV. One most noticeable metabolic abnormalities lipid reprogramming, which cells dysregulate obtain sufficient energy, building blocks for cell membranes, signaling molecules necessary invasion, metastasis, proliferation, survival. Moreover, proteins' stimulation production infected will probably a significant effect on oncogenesis. addition, lipids critical producing cellular epithelial-mesenchymal transition (EMT) process, therapy resistance HPV-related (HRCs). Therefore, essential HRC also be an important target approaches associated treatments during or development. This review study looked at role lipid-lowering drugs cancers.

Язык: Английский

---