Research and progress of ANO1-related diseases
ANO1相关疾病的研究进展
Introduce
介绍
Discovery and basic overview of ANO1
ANO1的发现和基本概述
Anoctamin 1 (ANO1), also known as TMEM16A, is a calcium-activated chloride channel (CaCC) that plays a critical role in various physiological processes[1]. Discovered through studies on epithelial ion transport, ANO1 mediates essential functions such as epithelial fluid secretion, gut motility, exocrine gland secretion, renal function, smooth muscle contraction, nociception, and metabolic regulation. ANO1 is also a key transduction channel in mediating Mas-related G-protein coupled receptor (Mrgpr)-dependent itch signals, making it essential for sensory perception and neural communication. Structurally, ANO1 forms a channel with an hourglass-shaped pore, and its activation is tightly regulated by intracellular calcium (Ca²⁺) levels.
Anoctamin 1 (ANO1)，也称为 TMEM16A，是一种钙激活氯离子通道 ( CaCC )，在各种生理过程中发挥着关键作用[1] 。通过上皮离子转运研究发现，ANO1 介导上皮液分泌、肠道运动、外分泌腺分泌、肾功能、平滑肌收缩、伤害感受和代谢调节等基本功能。 ANO1 也是介导 Mas 相关 G 蛋白偶联受体 ( Mrgpr ) 依赖性瘙痒信号的关键转导通道，使其对于感觉知觉和神经通讯至关重要。在结构上，ANO1 形成一个具有沙漏形孔的通道，其激活受到细胞内钙 (Ca²⁺) 水平的严格调节。
Recent studies have further elaborated on ANO1's unique structural and functional properties. Its pore structure, regulatory mechanisms, and interaction with intracellular calcium highlight its role as a critical component in maintaining cellular homeostasis. These findings establish ANO1 as a multifunctional ion channel with broad physiological and pathological significance[1], [2].
最近的研究进一步阐述了ANO1独特的结构和功能特性。其孔结构、调节机制以及与细胞内钙的相互作用突出了其作为维持细胞稳态的关键成分的作用。这些发现证实 ANO1 是一种具有广泛生理和病理意义的多功能离子通道[1], [2] 。
Background and importance of ANO1-related diseases
ANO1相关疾病的背景和重要性
A defining feature of ANO1 is its sensitivity to calcium ions. Advanced structural studies, including cryo-electron microscopy (cryo-EM) of mouse ANO1, have identified two Ca²⁺ binding sites located within the inner vestibule of the pore. Binding of Ca²⁺ to these sites induces conformational changes, particularly in the α6 transmembrane domain, that render the channel conductive to chloride ions[2]. This Ca²⁺ sensitivity is influenced by voltage and temperature, and its activation thresholds vary among ANO1 splice variants, ranging from approximately 100 to 400 nM.
ANO1 的一个决定性特征是它对钙离子的敏感性。先进的结构研究，包括小鼠 ANO1 的冷冻电子显微镜 (cryo-EM)，已经确定了位于孔内前庭内的两个 Ca2+ 结合位点。 Ca2+ 与这些位点的结合会引起构象变化，特别是在 α6 跨膜结构域中，从而使通道传导氯离子[2] 。这种 Ca2+ 敏感性受电压和温度的影响，其激活阈值因 ANO1 剪接变体而异，范围约为 100 至 400 nM。
In native cells, ANO1 operates within specialized microdomains or signaling complexes. For example, its interaction with caveolin-1 facilitates precise Ca²⁺-dependent signaling. Moreover, ANO1 interacts with diverse sources of calcium, including transient receptor potential (TRP) channels, voltage-gated calcium channels (VGCCs), inositol-1,4,5-trisphosphate (IP3) receptors on the endoplasmic reticulum, and store-operated calcium entry pathways. These interactions allow ANO1 to mediate localized and targeted calcium signaling[3].
在天然细胞中，ANO1 在专门的微结构域或信号复合物中发挥作用。例如，它与 Caveolin-1 的相互作用促进了精确的 Ca2+ 依赖性信号传导。此外，ANO1 与多种来源的钙相互作用，包括瞬时受体电位 (TRP) 通道、电压门控钙通道 (VGCC)、内质网上的肌醇 1,4,5-三磷酸 (IP3) 受体和钙库操作的受体。钙进入途径。这些相互作用使 ANO1 能够介导局部和靶向的钙信号传导[3] 。
In nociceptive neurons, ANO1 is activated by calcium influx through TRPV1 channels or by inflammatory mediators like serotonin and bradykinin. These mediators trigger G-protein coupled receptor (GPCR)-dependent IP3-receptor cascades, resulting in localized calcium release and subsequent ANO1 activation. Electrophysiological recordings and behavioral tests have confirmed the pivotal role of ANO1 in peripheral nerve function, including pain and itch perception[4].
在伤害性神经元中，ANO1 被通过 TRPV1 通道的钙流入或血清素和缓激肽等炎症介质激活。这些介质触发 G 蛋白偶联受体 (GPCR) 依赖性 IP3 受体级联反应，导致局部钙释放和随后的 ANO1 激活。电生理记录和行为测试已经证实ANO1在周围神经功能中的关键作用，包括疼痛和瘙痒感知[4] 。
Beyond its neural functions, ANO1 is critical for ciliogenesis and the maintenance of primary cilia. Dysregulation of ANO1 has been linked to various diseases. For instance, in polycystic kidney disease (PKD), ANO1 inhibition suppresses cyst formation and curtails dysregulated proliferative pathways in human PKD cells[5]. These findings underscore ANO1's involvement in diverse pathological processes, including ciliopathies, cancer, and inflammatory diseases[6].
除了其神经功能之外，ANO1 对于纤毛发生和初级纤毛的维持也至关重要。 ANO1 失调与多种疾病有关。例如，在多囊肾病 (PKD) 中，ANO1 抑制可抑制囊肿形成并减少人 PKD 细胞中失调的增殖途径[5] 。这些发现强调了 ANO1 参与多种病理过程，包括纤毛病、癌症和炎症性疾病[6] 。
Notably, ANO1 overexpression has been implicated in cancer progression. By modulating intracellular chloride and calcium dynamics, ANO1 influences cell proliferation, migration, and tumor metastasis. This highlights its potential as both a biomarker and a therapeutic target for cancer treatment. Similarly, ANO1 dysregulation contributes to cardiovascular diseases, such as hypertension, by altering vascular smooth muscle tone and endothelial function[7].
值得注意的是，ANO1 过度表达与癌症进展有关。通过调节细胞内氯和钙动力学，ANO1 影响细胞增殖、迁移和肿瘤转移。这凸显了其作为癌症治疗的生物标志物和治疗靶点的潜力。同样，ANO1 失调会改变血管平滑肌张力和内皮功能，从而导致高血压等心血管疾病[7] 。
Review Objectives
审查目标
This review systematically examines the role of ANO1 in different diseases and explores its potential as a therapeutic target. It aims to provide an in-depth analysis of ANO1's molecular mechanisms and functional regulation while identifying gaps in current research. By summarizing recent findings and proposing future research directions, this review seeks to offer a theoretical foundation and practical insights for advancing basic research and clinical translation related to ANO1-associated diseases[8].
本综述系统地研究了 ANO1 在不同疾病中的作用，并探讨了其作为治疗靶点的潜力。旨在深入分析ANO1的分子机制和功能调控，同时找出当前研究的差距。通过总结近期研究结果并提出未来研究方向，本文旨在为推进ANO1相关疾病相关基础研究和临床转化提供理论基础和实践见解[8] 。
In conclusion, understanding the complex mechanisms of ANO1 and its role in various diseases is critical for identifying novel therapeutic strategies. Its involvement in diverse processes, from ion homeostasis to signal transduction, positions ANO1 as a promising target for treating conditions such as cancer, kidney diseases, cardiovascular disorders, and sensory dysfunctions[6].
总之，了解 ANO1 的复杂机制及其在各种疾病中的作用对于确定新的治疗策略至关重要。它参与从离子稳态到信号转导的多种过程，使 ANO1 成为治疗癌症、肾脏疾病、心血管疾病和感觉功能障碍等疾病的有希望的靶点[6] 。
Recent advancements in structural and functional studies of ANO1 have paved the way for new therapeutic approaches. Targeted modulation of ANO1 activity, whether through small molecules, antibodies, or gene-editing technologies, holds significant potential for clinical translation. This review contributes to the growing body of knowledge about ANO1, providing a foundation for future innovations in medical science.
ANO1 结构和功能研究的最新进展为新的治疗方法铺平了道路。无论是通过小分子、抗体还是基因编辑技术，ANO1 活性的靶向调节都具有巨大的临床转化潜力。这篇综述有助于丰富有关 ANO1 的知识体系，为未来医学创新奠定基础。
2. Structure and function of ANO1
2. ANO1的结构和功能
2.1 Gene and protein structure
2.1 基因和蛋白质结构
ANO1, also known as TMEM16A, is a calcium-activated chloride channel (CaCC) critical for various physiological processes. Structural and mutagenesis studies have revealed that its channel pore is formed by transmembrane helices 3-8. These studies have also pinpointed specific amino acid residues involved in calcium binding, channel gating, and ion selectivity. The binding of calcium induces conformational changes that open the channel, allowing chloride ions to flow through. This structural insight into ANO1 provides a foundation for understanding its activation mechanisms and regulatory processes[9].
ANO1，也称为 TMEM16A，是一种钙激活氯离子通道 ( CaCC )，对各种生理过程至关重要。结构和诱变研究表明其通道孔由跨膜螺旋3-8形成。这些研究还确定了参与钙结合、通道门控和离子选择性的特定氨基酸残基。钙的结合引起构象变化，打开通道，允许氯离子流过。这种对 ANO1 的结构洞察为理解其激活机制和调控过程奠定了基础[9] 。
Beyond its role as an ion channel, ANO1 impacts cellular processes by modulating the distribution of membrane phosphoinositides and influencing endocytic transport. These functions are mediated through its control of intracellular chloride ion concentrations. Dysregulation of ANO1 activity has been associated with several pathological conditions. For instance, in hypertension, its overexpression in vascular smooth muscle cells contributes to increased vascular tone and elevated blood pressure. Similarly, ANO1 is implicated in tumorigenesis[10], as its overexpression promotes cell proliferation and cancer progression. These findings underscore the potential of ANO1 as a therapeutic target for diseases such as hypertension and cancer.
除了作为离子通道的作用之外，ANO1还通过调节膜磷酸肌醇的分布和影响内吞运输来影响细胞过程。这些功能是通过其对细胞内氯离子浓度的控制来介导的。 ANO1 活性失调与多种病理状况有关。例如，在高血压中，其在血管平滑肌细胞中的过度表达导致血管张力增加和血压升高。同样，ANO1 与肿瘤发生有关[10] ，因为它的过度表达会促进细胞增殖和癌症进展。这些发现强调了 ANO1 作为高血压和癌症等疾病的治疗靶点的潜力。
2.2 Molecular function
2.2分子功能
The activation of ANO1 is finely tuned by intracellular calcium concentrations ([Ca²⁺]), membrane voltage, and temperature. Under normal physiological conditions, thermal activation of ANO1 induces inward chloride ion currents, which are critical for maintaining cellular ion balance. Interestingly, calcium and voltage act synergistically to lower the threshold temperature for ANO1 activation. This synergy enables the channel to operate efficiently at near-physiological temperatures, enhancing its functional versatility[9], [11].
ANO1 的激活通过细胞内钙浓度 ([Ca²⁺])、膜电压和温度进行微调。在正常生理条件下，ANO1 的热激活会诱导内向氯离子电流，这对于维持细胞离子平衡至关重要。有趣的是，钙和电压协同作用，降低 ANO1 激活的阈值温度。这种协同作用使通道能够在接近生理温度下有效运行，增强其功能多功能性[9], [11] 。
Although intracellular calcium is a primary activator of ANO1, the channel can also be activated by voltage in the absence of calcium. The mechanisms underlying this voltage-dependent activation remain incompletely understood but suggest an additional layer of regulatory complexity. This dual mode of activation highlights ANO1's adaptability in responding to various physiological stimuli, making it a crucial component in multiple cellular processes.
尽管细胞内钙是 ANO1 的主要激活剂，但在没有钙的情况下，该通道也可以被电压激活。这种电压依赖性激活的机制仍然不完全清楚，但表明了额外的一层监管复杂性。这种双重激活模式凸显了 ANO1 对各种生理刺激作出反应的适应性，使其成为多种细胞过程的关键组成部分。
As a mammalian ion channel, ANO1 exhibits high efficiency in chloride ion transport, particularly in neuronal membranes. This efficiency, combined with its sensitivity to multiple regulatory inputs, positions ANO1 as a key player in maintaining cellular homeostasis and mediating physiological responses[6].
作为哺乳动物的离子通道，ANO1 在氯离子转运方面表现出高效率，特别是在神经元膜中。这种效率，加上其对多种调节输入的敏感性，使 ANO1 成为维持细胞稳态和介导生理反应的关键角色[6] 。
2.3 Expression and distribution
2.3 表达与分布
ANO1 is ubiquitously expressed across a wide range of tissues, reflecting its involvement in diverse physiological functions. In epithelial tissues, it mediates mucus secretion, playing a critical role in respiratory and gastrointestinal health[11]. In exocrine glands, ANO1 regulates secretion processes essential for maintaining digestive and reproductive system functions. Its role extends to the nervous system, where it modulates neuronal excitability, and to the cardiovascular system, where it influences cardiac repolarization and smooth muscle contraction[12].
ANO1 在多种组织中普遍表达，反映了其参与多种生理功能。在上皮组织中，它介导粘液分泌，在呼吸和胃肠道健康中发挥着关键作用[11] 。在外分泌腺中，ANO1 调节对于维持消化和生殖系统功能至关重要的分泌过程。它的作用延伸到神经系统，调节神经元兴奋性，并延伸到心血管系统，影响心脏复极和平滑肌收缩[12] 。
In vascular smooth muscle cells, ANO1 contributes to the regulation of vascular tone in various vascular beds, including the cerebral, coronary, mesenteric, and pulmonary arteries, as well as the aorta and portal vein. This regulation is vital for maintaining proper blood flow and pressure. Dysregulation of ANO1 in these tissues can lead to pathological outcomes, such as hypertension, heart failure, and vascular diseases[9].
在血管平滑肌细胞中，ANO1 有助于调节各种血管床的血管张力，包括脑动脉、冠状动脉、肠系膜动脉和肺动脉，以及主动脉和门静脉。这种调节对于维持适当的血流和压力至关重要。这些组织中 ANO1 的失调可导致病理结果，例如高血压、心力衰竭和血管疾病[9] 。
Moreover, ANO1's role in disease extends to cancer, where its overexpression has been associated with tumor growth and metastasis. These findings emphasize the channel's importance as both a physiological regulator and a potential therapeutic target. Its widespread expression and critical functions across multiple organ systems make ANO1 a focal point for research into disease mechanisms and therapeutic interventions[8].
此外，ANO1 在疾病中的作用延伸至癌症，其过度表达与肿瘤生长和转移有关。这些发现强调了该通道作为生理调节剂和潜在治疗靶点的重要性。其在多个器官系统中的广泛表达和关键功能使 ANO1 成为疾病机制和治疗干预研究的焦点[8] 。
By elucidating the structural, functional, and distributional characteristics of ANO1, researchers aim to develop targeted therapies for conditions ranging from vascular diseases to cancer, highlighting the channel's potential as a cornerstone in translational medicine[13].
通过阐明 ANO1 的结构、功能和分布特征，研究人员旨在开发针对从血管疾病到癌症等多种疾病的靶向疗法，突显该通道作为转化医学基石的潜力[13] 。
Diseases associated with ANO1
与 ANO1 相关的疾病
3.1 Tumor-related diseases
3.1 肿瘤相关疾病
ANO1 (also known as TMEM16A) is highly expressed in a wide variety of solid tumors, including head and neck cancer, breast cancer, pancreatic cancer, gastric cancer, esophageal cancer, and non-small cell lung cancer (NSCLC). This calcium-activated chloride channel (CaCC) is found in multiple cell types, such as secretory epithelia, smooth muscle cells, sensory neurons, and hepatocytes, and plays a significant role in cancer progression[1], [14].
ANO1（也称为 TMEM16A）在多种实体瘤中高表达，包括头颈癌、乳腺癌、胰腺癌、胃癌、食道癌和非小细胞肺癌 (NSCLC)。这种钙激活氯离子通道 ( CaCC ) 存在于多种细胞类型中，例如分泌上皮细胞、平滑肌细胞、感觉神经元和肝细胞，在癌症进展中发挥着重要作用[1], [14] 。
The overexpression and amplification of ANO1 are strongly associated with malignant tumor growth in various cancers, including parathyroid, gastrointestinal stromal, breast, lung, and prostate cancers. In NSCLC, a leading cause of cancer-related mortality, ANO1 overexpression is notably prevalent, making it a promising therapeutic target. Studies have demonstrated that the expression level of ANO1 is positively correlated with tumor stage, invasiveness, and poor prognosis, suggesting its potential as a prognostic marker[15], [16].
ANO1 的过度表达和扩增与各种癌症中的恶性肿瘤生长密切相关，包括甲状旁腺癌、胃肠道间质癌、乳腺癌、肺癌和前列腺癌。在癌症相关死亡的主要原因非小细胞肺癌中，ANO1 过度表达非常普遍，使其成为一个有前途的治疗靶点。研究表明ANO1的表达水平与肿瘤分期、侵袭性和不良预后呈正相关，提示其作为预后标志物的潜力[15]，[16] 。
Mechanistically, ANO1 promotes cancer cell proliferation, migration, and invasion by modulating calcium-dependent signaling pathways and regulating the tumor microenvironment. It has also been implicated in angiogenesis, supporting tumor growth by promoting blood vessel formation[17]. These findings position ANO1 as a critical player in oncogenesis and a potential focus for therapeutic intervention.
从机制上讲，ANO1通过调节钙依赖性信号通路和调节肿瘤微环境来促进癌细胞增殖、迁移和侵袭。它还与血管生成有关，通过促进血管形成来支持肿瘤生长[17] 。这些发现将 ANO1 定位为肿瘤发生的关键参与者以及治疗干预的潜在焦点。
3.2 Respiratory diseases
3.2呼吸系统疾病
ANO1 plays a pivotal role in regulating airway mucus secretion by controlling calcium-dependent chloride ion transport. This function is essential for maintaining normal respiratory physiology, but its dysregulation is linked to respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF).
ANO1 通过控制钙依赖性氯离子转运，在调节气道粘液分泌方面发挥着关键作用。该功能对于维持正常的呼吸生理机能至关重要，但其失调与哮喘、慢性阻塞性肺病 (COPD) 和囊性纤维化 (CF) 等呼吸系统疾病有关。
In asthma and COPD, ANO1 overactivity exacerbates airway smooth muscle contraction and mucus secretion, leading to increased airway obstruction and respiratory difficulty[18]. Collaborative interactions between ANO1 and cystic fibrosis transmembrane conductance regulator (CFTR) are critical for airway mucus secretion. Notably, ANO1 can act as an alternative chloride channel to partially compensate for CFTR dysfunction in CF patients, thereby aiding in mucus clearance and improving respiratory function[19].
在哮喘和慢性阻塞性肺病中，ANO1过度活跃会加剧气道平滑肌收缩和粘液分泌，导致气道阻塞增加和呼吸困难[18] 。 ANO1 和囊性纤维化跨膜电导调节因子 (CFTR) 之间的协同相互作用对于气道粘液分泌至关重要。值得注意的是，ANO1 可以作为替代氯离子通道，部分补偿 CF 患者的 CFTR 功能障碍，从而帮助清除粘液并改善呼吸功能[19] 。
Therapeutically, targeting ANO1 to modulate its activity holds promise for treating respiratory diseases. ANO1 inhibition may reduce mucus hypersecretion and smooth muscle contraction in asthma and COPD, while its activation could enhance chloride ion transport in CF, alleviating mucus buildup and related complications.
在治疗上，以 ANO1 为靶点来调节其活性有望治疗呼吸系统疾病。 ANO1 抑制可能会减少哮喘和 COPD 中的粘液过度分泌和平滑肌收缩，而其激活可以增强 CF 中的氯离子转运，从而减轻粘液积聚和相关并发症。
3.3 Digestive diseases
3.3 消化系统疾病
ANO1 has emerged as a key player in gastrointestinal (GI) motility and other digestive disorders. It serves as a specific marker of interstitial cells of Cajal (ICCs), which are essential for generating slow waves in gastric and intestinal muscles, a prerequisite for normal gut motility. Constitutive knockout of ANO1 results in the loss of these slow waves, leading to GI motility disorders characterized by symptoms of functional bowel obstruction[2], [6].
ANO1 已成为胃肠道 (GI) 运动和其他消化系统疾病的关键参与者。它是卡哈尔间质细胞 (ICC) 的特异性标记物，对于在胃和肠肌肉中产生慢波至关重要，而慢波是正常肠道蠕动的先决条件。 ANO1 的组成型敲除会导致这些慢波的丧失，从而导致以功能性肠梗阻症状为特征的胃肠道运动障碍[2], [6] 。
Additionally, ANO1 expression within the esophageal basal zone is positively correlated with disease severity, such as eosinophilic esophagitis. Mechanistic studies using in vitro esophageal epithelial models have shown that ANO1 undergoes chromatin modification and upregulation following IL-13 stimulation. This upregulation drives Cl⁻ transport, basal cell proliferation, and esophageal epithelial remodeling by modulating TP63 expression and phosphorylated cyclin-dependent kinase 2 levels[20].
此外，食管基底区内的 ANO1 表达与疾病严重程度呈正相关，例如嗜酸性食管炎。使用体外食管上皮模型的机制研究表明，ANO1 在 IL-13 刺激后经历染色质修饰和上调。这种上调通过调节 TP63 表达和磷酸化细胞周期蛋白依赖性激酶 2 水平来驱动 Cl⁻ 转运、基底细胞增殖和食管上皮重塑[20] 。
These findings highlight ANO1's dual role in both maintaining normal gastrointestinal function and contributing to disease pathology. Targeting ANO1 may offer therapeutic benefits for conditions such as eosinophilic esophagitis, motility disorders, and other GI diseases.
这些发现强调了 ANO1 在维持正常胃肠功能和促进疾病病理学方面的双重作用。靶向 ANO1 可能为嗜酸性粒细胞性食管炎、动力障碍和其他胃肠道疾病等疾病提供治疗益处。
3.4 Cardiovascular Diseases
3.4心血管疾病
ANO1 regulates the contractile function of vascular smooth muscle cells by mediating calcium-dependent chloride ion transport. Abnormal ANO1 activity can lead to vasospasm, increased vascular tone, and elevated blood pressure, making it a contributor to hypertension[21].
ANO1 通过介导钙依赖性氯离子转运来调节血管平滑肌细胞的收缩功能。 ANO1 活性异常可导致血管痉挛、血管张力增加和血压升高，从而导致高血压[21] 。
Moreover, ANO1 is implicated in the pathogenesis of atherosclerosis through its involvement in inflammatory and oxidative stress-mediated signaling pathways. These pathways promote the formation of atherosclerotic plaques, contributing to vascular disease progression.
此外，ANO1 通过参与炎症和氧化应激介导的信号通路而参与动脉粥样硬化的发病机制。这些途径促进动脉粥样硬化斑块的形成，导致血管疾病的进展。
In cardiomyocytes, ANO1 plays a crucial role in forming and conducting myocardial action potentials by regulating intracellular calcium signaling. Dysfunctional ANO1 activity can disrupt this process, leading to arrhythmias and other cardiovascular disorders[22].
在心肌细胞中，ANO1 通过调节细胞内钙信号传导，在形成和传导心肌动作电位方面发挥着至关重要的作用。 ANO1 活性功能失调会破坏这一过程，导致心律失常和其他心血管疾病[22] 。
Given its multifaceted role in cardiovascular physiology and pathology, ANO1 represents a potential target for therapeutic intervention. Modulating its activity could help manage hypertension, prevent atherosclerosis, and restore normal cardiac rhythm in patients with arrhythmias.
鉴于 ANO1 在心血管生理学和病理学中的多方面作用，ANO1 代表了治疗干预的潜在靶点。调节其活性可以帮助控制高血压、预防动脉粥样硬化并恢复心律失常患者的正常心律。
4. Research methods and technical progress of ANO1
4 ANO1的研究方法及技术进展
4.1 Molecular biotechnology
4.1 分子生物技术
The expression of ANO1 is regulated at multiple levels, including transcriptional, translational, and post-translational stages. Among the key regulators, signal transducer and activator of transcription (STAT) transcription factors play a significant role in controlling ANO1 gene transcription. Additionally, recent findings have revealed ANO1 as a mechanosensitive channel in osteoclasts, where its expression and activity are influenced by mechanical stimuli[10].
ANO1 的表达在多个水平上受到调节，包括转录、翻译和翻译后阶段。在关键调控因子中，信号转导子和转录激活子（STAT）转录因子在控制ANO1基因转录中发挥着重要作用。此外，最近的研究结果表明ANO1是破骨细胞中的机械敏感通道，其表达和活性受到机械刺激的影响[10] 。
For instance, osteoclast activity, crucial for bone remodeling, is modulated under different mechanical treatments. Under conditions such as 12 dyn/cm² fluid shear stress or 4 g hypergravity, osteoclast activity is inhibited, accompanied by decreased ANO1 expression. Conversely, simulated microgravity promotes osteoclast activity and increases ANO1 expression levels. These findings highlight the mechanosensitivity of ANO1 and its critical role in responding to mechanical cues in osteoclasts, shedding light on potential therapeutic approaches for bone-related disorders[23].
例如，对于骨重塑至关重要的破骨细胞活性在不同的机械治疗下受到调节。在12 dyn /cm²流体剪切应力或4 g超重力等条件下，破骨细胞活性受到抑制，同时ANO1表达减少。相反，模拟微重力会促进破骨细胞活性并增加 ANO1 表达水平。这些发现强调了ANO1 的机械敏感性及其在破骨细胞中响应机械信号的关键作用，为骨相关疾病的潜在治疗方法提供了线索[23] 。
4.2 Pharmacological studies
4.2 药理学研究
The abnormal expression or dysfunction of ANO1 significantly impacts the physiological functions of various systems by influencing ion transport, cell proliferation, migration, and secretion. As a calcium-activated chloride channel, ANO1 is primarily regulated by intracellular calcium levels. Disturbances in calcium signaling, which serve as the pathological basis of many diseases, directly affect ANO1 function[23].
ANO1的异常表达或功能障碍通过影响离子转运、细胞增殖、迁移和分泌而显着影响各个系统的生理功能。作为钙激活的氯离子通道，ANO1 主要受细胞内钙水平的调节。钙信号传导紊乱直接影响ANO1功能[23] ，是许多疾病的病理基础。
Beyond calcium activation, ANO1 can modulate the physical and chemical environment around cells through ion transport[24]. This "microenvironmental regulation" alters factors such as pH and ionic gradients, influencing disease progression. Furthermore, ANO1's role is not restricted to ion channel activity; it participates in diverse pathological processes by interacting with other signaling molecules, highlighting its versatility as both an ion channel and a signaling regulator.
除了钙激活之外，ANO1 还可以通过离子传输调节细胞周围的物理和化学环境[24] 。这种“微环境调节”会改变 pH 值和离子梯度等因素，从而影响疾病进展。此外，ANO1 的作用不仅限于离子通道活性；它通过与其他信号分子相互作用参与多种病理过程，突出了其作为离子通道和信号调节剂的多功能性。
For example, ANO1 is implicated in cancer by promoting cell proliferation and migration, as well as in diseases involving excessive secretion, such as in the airway and gastrointestinal tract. These roles make it a compelling target for pharmacological intervention[21].
例如，ANO1 通过促进细胞增殖和迁移而与癌症有关，以及涉及过度分泌的疾病，例如气道和胃肠道疾病。这些作用使其成为药物干预的引人注目的目标[21] 。
4.3 Clinical research
4.3 临床研究
Emerging evidence suggests that reducing ANO1 protein levels, rather than directly and rapidly inhibiting channel activity, may offer advantages in treating certain diseases, such as cancer. For instance, small molecule inhibitors like T16Ainh-A01 and Ani9 have been developed to selectively block ANO1 activity, showing promise in inhibiting tumor cell proliferation and migration, as well as reducing excessive secretions in the airway and gastrointestinal systems[24].
新的证据表明，降低 ANO1 蛋白水平，而不是直接快速抑制通道活性，可能在治疗某些疾病（例如癌症）方面具有优势。例如，T16Ainh-A01和Ani9等小分子抑制剂已被开发用于选择性阻断ANO1活性，在抑制肿瘤细胞增殖和迁移以及减少气道和胃肠系统中的过度分泌方面显示出前景[24] 。
Natural compounds, including plant-derived extracts, have also been found to regulate ANO1 activity, opening new avenues for the development of low-toxicity therapeutic agents. These natural compounds could serve as alternative or complementary approaches in targeting ANO1 function, particularly for patients requiring long-term treatment[21].
天然化合物，包括植物提取物，也被发现可以调节 ANO1 活性，为开发低毒性治疗药物开辟了新途径。这些天然化合物可以作为靶向 ANO1 功能的替代或补充方法，特别是对于需要长期治疗的患者[21] 。
Advanced molecular techniques are also being explored to modulate ANO1 expression and activity. RNA interference (RNAi) technologies, such as small interfering RNA (siRNA), and CRISPR/Cas9 genome-editing techniques are being employed to specifically reduce ANO1 expression levels in diseases associated with its overexpression, such as cancer. On the other hand, in loss-of-function conditions like cystic fibrosis[25], [26], gene therapy approaches using adenovirus vectors to deliver the normal ANO1 gene have shown potential in restoring its function[27].
先进的分子技术也正在探索调节 ANO1 的表达和活性。 RNA 干扰 (RNAi) 技术，例如小干扰 RNA (siRNA) 和 CRISPR/Cas9 基因组编辑技术，可用于特异性降低与其过度表达相关的疾病（例如癌症）中的 ANO1 表达水平。另一方面，在囊性纤维化等功能丧失的情况下[25]、[26] ，使用腺病毒载体传递正常ANO1基因的基因治疗方法已显示出恢复其功能的潜力[27] 。
These findings underscore the broad therapeutic potential of ANO1 modulation across various diseases. Targeted inhibition of ANO1 holds promise for diseases characterized by overexpression or hyperactivity, while gene delivery approaches could restore ANO1 function in diseases caused by its deficiency.
这些发现强调了 ANO1 调节在各种疾病中的广泛治疗潜力。 ANO1 的靶向抑制有望治疗以过度表达或过度活跃为特征的疾病，而基因递送方法可以恢复 ANO1 缺陷引起的疾病的功能。
5. Prospects and challenges of ANO1 as a therapeutic target
5. ANO1作为治疗靶点的前景与挑战
5.1 Potential of targeted therapies
5.1 靶向治疗的潜力
Specific high expression: ANO1 is highly expressed in a variety of solid tumors (such as head and neck cancer, pancreatic cancer, and gastric cancer), and is significantly correlated with tumor proliferation and metastasis, providing an ideal target for tumor therapy. In some non-neoplastic diseases, such as cystic fibrosis and gastrointestinal motility disorders, abnormal activation or inhibition of ANO1 directly affects pathological processes[21]. Multiple pathological functions: ANO1 is involved in the occurrence and development of various diseases by regulating cell proliferation, migration, ion balance and other mechanisms. Its versatility makes it a central target that can influence multiple pathologic pathways. Advances in molecular pharmacology: The development of ANO1 inhibitors and activators continues to make progress, and targeted therapies are gradually enriched, laying a foundation for clinical application[22].
特异性高表达：ANO1在多种实体瘤（如头颈癌、胰腺癌、胃癌）中高表达，与肿瘤增殖和转移显着相关，为肿瘤治疗提供了理想的靶点。在一些非肿瘤性疾病中，如囊性纤维化和胃肠动力障碍，ANO1的异常激活或抑制直接影响病理过程[21] 。多重病理功能：ANO1通过调节细胞增殖、迁移、离子平衡等机制参与多种疾病的发生和发展。它的多功能性使其成为可以影响多种病理途径的中心靶点。分子药理学进展：ANO1抑制剂和激活剂的研发不断取得进展，靶向治疗逐渐丰富，为临床应用奠定了基础[22] 。
5.2 Challenges and Problems
5.2 挑战和问题
The mechanism of ANO1 in different diseases is complex and varied while its pathological mechanism is not fully understood. For example, it not only promotes cell proliferation and migration in tumors, but also participates in tumor microenvironment regulation[28]. More research is needed to clarify the specific function and mechanism of ANO1 in specific diseases. The calcium-dependent regulation of ANO1 and its interactions with other ion channels and signaling pathways are not fully understood[24]. Functional heterogeneity ANO1 has a high degree of functional heterogeneity in different tissues and cells. For example, high expression in tumors promotes progression, but may exhibit protective function in the nervous system and gastrointestinal tract. In the same disease, there are also significant differences in the expression level and activity of ANO1 among patients, which adds to the complexity of the study. Synergies with other channels The synergies between ANO1 and CFTR (Cystic fibrosis Transmembrane Regulatory Factor) plasma channels are particularly important in respiratory and digestive diseases, but the specific interaction mechanisms have not been fully revealed[29].
ANO1在不同疾病中的作用机制复杂多样，其病理机制尚不完全清楚。例如，它不仅促进肿瘤中的细胞增殖和迁移，还参与肿瘤微环境的调节[28] 。需要更多的研究来阐明ANO1在特定疾病中的具体功能和机制。 ANO1 的钙依赖性调节及其与其他离子通道和信号通路的相互作用尚未完全了解[24] 。功能异质性 ANO1在不同组织和细胞中具有高度的功能异质性。例如，肿瘤中的高表达促进进展，但可能在神经系统和胃肠道中表现出保护功能。在同一疾病中，患者之间ANO1的表达水平和活性也存在显着差异，这增加了研究的复杂性。与其他通道的协同作用ANO1与CFTR（囊性纤维化跨膜调节因子）血浆通道之间的协同作用在呼吸系统和消化系统疾病中尤为重要，但具体的相互作用机制尚未完全揭示[29] 。
5.3 Future research direction
5.3 未来研究方向
Precise analysis of diverse functions, systematic study of the physiological and pathological functions of ANO1 in different tissues and cell types. To explore the interaction mechanism of ANO1 with other ion channels (such as CFTR) and signaling pathways (PI3K/AKT, MAPK/ERK), and clarify its specific role in different diseases. Multidimensional exploration of the pathological mechanism, and further analysis of how ANO1 promotes cancer development by regulating cell proliferation, migration, invasion and tumor microenvironment in tumors[30]. In non-neoplastic diseases (e.g., cystic fibrosis, gastrointestinal motility disorders), investigate how ANO1 dysfunctions affect disease progression. Understanding the molecular mechanism of calcium signaling regulation, calcium dependence is the key to ANO1 activation. In the future, it is necessary to clarify the relationship between calcium signal and ANO1 activity, and how to regulate its function through calcium signal to treat diseases. Highly selective inhibitors and activators, novel small molecule inhibitors and activators are designed based on structural biology to improve specificity and reduce side effects[31]. Develop regulators that can specifically target specific tissues or pathological states to avoid systemic off-target effects. For the screening of natural compounds, high-throughput screening technology is used to find compounds with ANO1 regulation ability from natural products to provide candidate molecules for low-toxicity drugs. Conduct combination therapy strategies to explore the synergies of ANO1 inhibitors or activators with other therapies (e.g., immunotherapy, chemotherapy, gene therapy)[32].
精准分析多种功能，系统研究ANO1在不同组织和细胞类型中的生理和病理功能。探讨ANO1与其他离子通道（如CFTR）和信号通路（PI3K/AKT、MAPK/ERK）的相互作用机制，阐明其在不同疾病中的具体作用。多维度探索病理机制，进一步分析ANO1如何通过调节肿瘤内细胞增殖、迁移、侵袭和肿瘤微环境来促进肿瘤发展[30] 。在非肿瘤性疾病（例如囊性纤维化、胃肠道运动障碍）中，研究 ANO1 功能障碍如何影响疾病进展。了解钙信号调节的分子机制，钙依赖性是ANO1激活的关键。未来有必要明确钙信号与ANO1活性的关系，以及如何通过钙信号调节其功能来治疗疾病。高选择性抑制剂和激活剂、新型小分子抑制剂和激活剂是基于结构生物学设计的，以提高特异性并减少副作用[31] 。开发可以专门针对特定组织或病理状态的调节剂，以避免系统性脱靶效应。对于天然化合物的筛选，利用高通量筛选技术从天然产物中寻找具有ANO1调节能力的化合物，为低毒药物提供候选分子。开展联合治疗策略，探索ANO1抑制剂或激活剂与其他疗法（例如免疫疗法、化疗、基因疗法）的协同作用[32] 。
6. Summary and prospect
六、总结与展望
6.1 Summary
6.1 总结
Anoctamin 1 (ANO1), also known as TMEM16A, is a calcium-activated chloride channel (CaCC) that plays essential roles in physiological processes such as epithelial secretion, smooth muscle contraction, and sensory signaling. Structurally, ANO1 forms a channel regulated by intracellular calcium levels, voltage, and temperature. Dysregulation of ANO1 has been implicated in various diseases, including cancer, respiratory disorders, and cardiovascular conditions. Mechanistically, ANO1 contributes to disease progression by altering ion transport, cell proliferation, and migration.
Anoctamin 1 (ANO1)，也称为 TMEM16A，是一种钙激活氯通道 ( CaCC )，在上皮分泌、平滑肌收缩和感觉信号传导等生理过程中发挥重要作用。在结构上，ANO1 形成一个受细胞内钙水平、电压和温度调节的通道。 ANO1 失调与多种疾病有关，包括癌症、呼吸系统疾病和心血管疾病。从机制上讲，ANO1 通过改变离子转运、细胞增殖和迁移来促进疾病进展。
Pharmacological studies have identified inhibitors like T16Ainh-A01 and Ani9, which effectively target ANO1 activity, demonstrating therapeutic potential for cancer and hypersecretion disorders. Additionally, natural compounds and molecular techniques like RNA interference (siRNA) and CRISPR/Cas9 have emerged as promising tools for modulating ANO1 expression. In cystic fibrosis, gene therapy to restore ANO1 function shows promise. Despite these advancements, the functional heterogeneity of ANO1 across tissues and its interaction with other signaling pathways remain significant challenges.
药理学研究已经确定了 T16Ainh-A01 和 Ani9 等抑制剂，它们可以有效靶向 ANO1 活性，证明了对癌症和分泌过多性疾病的治疗潜力。此外，RNA 干扰 (siRNA) 和 CRISPR/Cas9 等天然化合物和分子技术已成为调节 ANO1 表达的有前途的工具。在囊性纤维化中，恢复 ANO1 功能的基因疗法显示出希望。尽管取得了这些进展，ANO1 跨组织的功能异质性及其与其他信号通路的相互作用仍然是重大挑战。
6.2 Outlook
6.2 展望
Future research should focus on uncovering the molecular mechanisms underlying ANO1 regulation and its interaction with calcium signaling and other ion channels. A precise understanding of its roles in various tissues and disease contexts will guide therapeutic developments. Designing highly selective small molecule inhibitors and activators, as well as tissue-specific regulators, will help reduce systemic side effects.
未来的研究应侧重于揭示 ANO1 调节的分子机制及其与钙信号传导和其他离子通道的相互作用。准确了解其在各种组织和疾病背景中的作用将指导治疗的发展。设计高度选择性的小分子抑制剂和激活剂以及组织特异性调节剂将有助于减少全身副作用。
The development of combination therapy strategies, integrating ANO1 modulation with chemotherapy, immunotherapy, or gene therapy, holds promise for enhanced efficacy. Additionally, high-throughput screening of natural compounds can expand the repertoire of low-toxicity therapeutic candidates. Advances in structural biology will further aid in the creation of targeted drugs.
联合治疗策略的开发，将 ANO1 调节与化疗、免疫疗法或基因疗法相结合，有望提高疗效。此外，天然化合物的高通量筛选可以扩大低毒性候选治疗药物的范围。结构生物学的进步将进一步有助于靶向药物的开发。
Overall, ANO1 represents a versatile therapeutic target, with potential applications spanning oncology, respiratory diseases, and beyond. Addressing its complexity and functional diversity will be key to translating these findings into clinical benefits.
总体而言，ANO1 代表了一种多功能的治疗靶点，其潜在应用涵盖肿瘤学、呼吸系统疾病等。解决其复杂性和功能多样性是将这些发现转化为临床益处的关键。
7. reference
7.参考
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