Kazemi Kimia, Fadl Asmaa, Sperandio Felipe F, Leask Andrew
College of Dentistry, University of Saskatchewan, 105 Wiggins Road, Saskatoon, SK S7N 5E4, Canada.
Dent J (Basel). 2025 Aug 12;13(8):364. doi: 10.3390/dj13080364.
The areca nut (AN) is chewed by approximately 600 million people worldwide. Among AN chewers, ~5% develop oral submucosal fibrosis (OSF), a progressive fibrotic disorder of the oral cavity. OSF is characterized by subepithelial fibrosis and mucosal rigidity, leading to restricted mouth opening, difficulty in mastication, deglutition, and speech. These impairments severely compromise oral hygiene and routine dental care, diminishing patients' quality of life. At least 4% of OSF patients develop oral cancer. The prevalence of OSF correlates with AN chewing, particularly when accompanied by other risk factors such as tobacco use. The International Agency for Research on Cancer has identified chronic chemical and mechanical irritation of the oral mucosa from AN chewing as a major cause of OSF. The active chemical ingredients of AN include alkaloids such as arecoline, flavonoids, and tannins. Of these, arecoline is considered the most potent fibrogenic agent. In vitro, arecoline induces cultured fibroblasts to differentiate into highly contractile α-smooth muscle actin (α-SMA)-expressing myofibroblasts, the effector cells of fibrosis, and to express profibrotic markers and mediators, including transforming growth factor-β 1 (TGF-β1) and cellular communication network factor 2 (CCN2), which is associated with malignant progression of OSF. In vivo, mice exposed to AN extract or arecoline show submucosal collagen accumulation and myofibroblast differentiation, concomitant with upregulated pro-fibrotic gene (TGF-β1, Col1A1, α-SMA) expression. Although myofibroblasts can be seen in OSF patient-derived samples, substantial disease heterogeneity exists, which has thus far hindered the generation of high-quality data necessary to gain insights into underlying mechanisms and disease progression. Consequently, treatment options for OSF are limited and primarily symptomatic. Collectively, evidence from human and animal studies establishes OSF as an AN-induced fibrotic disorder and underscores the urgent need for mechanism-focused research to identify reliable diagnostic markers and therapeutic targets to address its growing global burden.
全世界约有6亿人嚼食槟榔。在嚼食槟榔者中，约5%会患上口腔黏膜下纤维化（OSF），这是一种口腔的进行性纤维化疾病。OSF的特征是上皮下纤维化和黏膜僵硬，导致张口受限、咀嚼、吞咽及言语困难。这些功能障碍严重影响口腔卫生和常规牙科护理，降低患者的生活质量。至少4%的OSF患者会发展为口腔癌。OSF的患病率与嚼食槟榔有关，尤其是在伴有烟草使用等其他风险因素时。国际癌症研究机构已确定嚼食槟榔对口腔黏膜造成的慢性化学和机械刺激是OSF的主要病因。槟榔的活性化学成分包括生物碱如槟榔碱、黄酮类化合物和单宁。其中，槟榔碱被认为是最有效的促纤维化剂。在体外，槟榔碱可诱导培养的成纤维细胞分化为高收缩性且表达α平滑肌肌动蛋白（α-SMA）的肌成纤维细胞，即纤维化的效应细胞，并表达促纤维化标志物和介质，包括转化生长因子-β1（TGF-β1）和细胞通讯网络因子2（CCN2），后者与OSF的恶性进展有关联。在体内实验中，接触槟榔提取物或槟榔碱的小鼠会出现黏膜下胶原积聚和肌成纤维细胞分化，并伴随促纤维化基因（TGF-β1、Col1A1、α-SMA）表达上调情况。尽管在OSF患者来源样本中可观察到肌成纤维细胞，但存在显著的疾病异质性，这迄今为止阻碍了获取深入了解潜在机制和疾病进展所需的高质量数据。因此，OSF的治疗选择有限，且主要是对症治疗。总体而言，来自人类和动物研究的证据表明OSF是一种由槟榔诱发的纤维化疾病，并凸显了迫切需要开展以机制为重点的研究，以确定可靠的诊断标志物和治疗靶点，从而应对其日益加重的全球负担。
