Discovered in 1996, PCSK7 is the seventh of the nine-membered proprotein convertase subtilisin-kexin (PCSK) family. This article reviews the various aspects of the multifaceted biology of PCSK7 and what makes it an exciting new target for metabolic dysfunction-associated steatotic liver disease (MASLD) affecting ∼30% of the population globally, dyslipidemia, cardiovascular disease (CVD), and likely cancer/metastasis. We will systematically review and discuss all the available epidemiological data, structural, cell biology, and in vivo evidence that eventually led to the discovery of PCSK7 as a novel post-translational regulator of apolipoprotein B. Interestingly, PCSK7 is the only convertase, other than PCSK9, that exhibits non-canonical/non-enzymatic functions, which will be amply described in this review. The data so far suggested that PCSK7 is a potential safe target in MASLD treatment. This was based on human epidemiological data, as well as mouse Pcsk7 knockout and mRNA translation inhibition using hepatocyte-targeted antisense oligonucleotides following a diet-induced MASLD. Additionally, of all the 9 convertases only the gene deletion of Pcsk7 and/or Pcsk9 in mice leads to healthy and fertile animals with no apparent deleterious consequences, suggesting that their pharmacological targeting is likely safe. Accordingly, the synergistic effects of inhibiting both PCSK7 and PCSK9 in a clinical setting may represent a novel therapy for various diseases. We believe that the current surge in oligonucleotide therapy, with many FDA-approved oligonucleotide-based drugs now available in the clinics, and the urgent need for novel MASLD therapeutics present an opportune moment for this timely review article.

中文翻译：

---

PCSK7 的生物学和临床意义。


PCSK7 于 1996 年被发现，是九元前蛋白转化酶枯草杆菌蛋白酶-kexin （PCSK） 家族的第七个。本文回顾了 PCSK7 多方面生物学的各个方面，以及是什么使其成为代谢功能障碍相关脂肪性肝病 （MASLD） 的令人兴奋的新靶点，该病影响了全球约 30% 的人口、血脂异常、心血管疾病 （CVD） 和可能的癌症/转移。我们将系统地回顾和讨论所有可用的流行病学数据、结构、细胞生物学和体内证据，这些证据最终导致发现 PCSK7 作为载脂蛋白 B 的新型翻译后调节因子。有趣的是，PCSK7 是除 PCSK9 之外唯一表现出非经典/非酶功能的转化酶，这将在这篇综述中得到充分描述。迄今为止的数据表明，PCSK7 是 MASLD 治疗中的潜在安全靶点。这是基于人类流行病学数据，以及在饮食诱导的 MASLD 后使用肝细胞靶向反义寡核苷酸的小鼠 Pcsk7 敲除和 mRNA 翻译抑制。此外，在所有 9 种转化酶中，只有小鼠中 Pcsk7 和/或 Pcsk9 的基因缺失导致动物健康和可育，没有明显的有害后果，表明它们的药理学靶向可能是安全的。因此，在临床环境中抑制 PCSK7 和 PCSK9 的协同作用可能代表各种疾病的新疗法。我们相信，目前寡核苷酸疗法的激增，许多 FDA 批准的基于寡核苷酸的药物现已在临床上可用，以及对新型 MASLD 疗法的迫切需求，为这篇及时的综述文章提供了合适的时机。