Keloids are pathological scars caused by skin injury and irritation. These are benign skin tumors characterized by hyperproliferation of fibroblasts and excessive deposition of collagen fibers (Limandjaja et al., 2020). Keloids can extend beyond the area of injury and invade the adjacent normal skin (Tan et al., 2019). Keloids significantly reduce people’s life quality by causing esthetic deformity, pruritus, hyperesthesia, and pain (Olaitan, 2009). Conventional treatment ways, consisting of surgical excision, cryotherapy, topical steroids, and laser therapy, remain unsatisfactory, and relapse is common (Park et al., 2014; Berman et al., 2017; Ekstein et al., 2021). It is urgent to understand the mechanism underlying keloid formation for better treatment approaches.

Circular RNAs (circRNAs) are a new type of non-coding RNAs originating from precursor messenger RNAs. Different from linear RNA, circRNAs are single-stranded RNAs that form a closed loop. CircRNAs lack 5′ and 3’ ends, which makes them more stable (Jeck et al., 2013; Kristensen et al., 2019). Since circRNAs were first discovered in plant viroids in 1976, thousands of circRNAs across species have been identified (Sanger et al., 1976; Vo et al., 2019). CircRNAs were considered the byproduct of wrong splicing for a long time. Recent research has confirmed that circRNAs play a significant role in various biological and pathological processes, including cell viability, migration, and apoptosis (Memczak et al., 2013; Di Timoteo et al., 2020). CircRNAs exert their biological functions at the post-transcriptional level, including in transcription and splicing, interfering with miRNA activities or signaling pathways, and serving as translation templates (Chen, 2020). In particular, circRNAs contain various binding sites for miRNAs and absorb miRNAs like a sponge, serving as competitive endogenous RNAs (ceRNAs) or miRNA sponges (Memczak et al., 2013). Emerging studies have demonstrated that the deregulated circRNA–miRNA–mRNA interaction network plays a key role in the development of many diseases (Liang et al., 2020; Sakshi et al., 2021).

Increasing evidence has highlighted the role of ncRNAs (mainly miRNAs and lncRNAs) in the pathogenesis of keloids (Babalola et al., 2013). Recently, several publications also indicated that circRNAs contribute to keloid development. The discovery of circRNAs changed the current understanding of the biology of keloids. It is crucial to elucidate a circRNA–miRNA–mRNA network to understand the pathological mechanism of keloids. In the present review, we summarize the aberrant expression of regulatory roles of circRNAs in keloids. We discuss the potential clinical application of circRNAs in the diagnosis and treatment of keloid.

Genetic, epigenetic, and environmental factors are crucial in molecular pathogenesis underlying keloid formation (He et al., 2017). The inheritance pattern of keloids may follow autosomal dominance with incomplete penetrance. In addition, keloids tend to be polygenic, not following a simple Mendelian monogenic manner. Individuals with dark skin color show an increased prevalence of keloids with an estimated incidence of 4%–16%, 15 times higher than in Caucasian populations. NEDD4 was proven to be a candidate gene in Chinese Han and Japanese populations (Fujita et al., 2019). Epigenetic modifications are composed of DNA methylations, histone modifications, and non-coding RNA regulations. Non-coding RNAs are mainly composed of three types, microRNAs—miRNAs, long non-coding RNAs—lncRNAs, and circular RNAs—circRNAs. Emerging research showed that epigenetics plays a crucial role in the molecular pathogenesis of keloids. Epigenetic modification is considered to be an important regulator in the initial and sustained activation of keloid fibroblasts (Lv et al., 2020).

High-throughput sequencing and gene microarray have demonstrated aberrant expression profiles of circRNAs in keloid tissue and fibroblasts (Table 1). The altered expression profiles of circRNAs in keloid tissue may contribute to the etiology and pathophysiology of keloids by impacting signaling pathways relevant to the scaring process.

In a high-throughput sequencing research, Zhang et al. identified 411 differentially expressed (DE) circRNAs performed in three HKFs and normal dermal fibroblasts, with 206 circRNAs upregulated and 205 circRNAs downregulated. Bioinformatics analyses showed that 411 DE circRNAs mainly participated in cell apoptosis and focal adhesion processes, as well as PI3K-Akt, Rap1, and metabolic signaling pathways (Zhang et al., 2020a). Shi et al. used a circRNA microarray assay to determine circRNA expression in keloid tissue compared with paired normal skin tissue. They showed that 52 circRNAs were upregulated and 24 downregulated in keloids (Shi et al., 2020). In addition, further analysis found that circRNAs could interact with miR-29a, miR-23a-5p, and miR-1976 (Shi et al., 2020). Wang et al. performed high-throughput sequencing research in keloid tissue compared with normal skin tissue. Among 154 DE circRNAs, 81 circRNAs were upregulated and 73 circRNAs were downregulated (Wang et al., 2019). Li et al. performed high-throughput sequencing and showed that circRNAs might act as ceRNAs in the development of human hypertrophic scars (Li et al., 2018). Pang et al. performed microarray technology in four patient-derived keloid dermal fibroblasts (KDFs) compared with normal dermal fibroblasts (NDFs) (Pang et al., 2022). They detected a total of 327 DE circRNAs, with 195 upregulated and 132 downregulated circRNAs. The DE circRNAs were mainly enriched in cell function of the cytoskeleton, tight junctions, axonal guidance, and morphogenesis of the epithelium.

Myofibroblasts derived from quiescent resident skin fibroblasts are the principal cell type responsible for extracellular matrix (ECM) accumulation. The imbalance between fibroblast proliferation and apoptosis is the cytological basis for the continuous proliferation of keloids, and it highlights the epigenetic contribution to keloid formation by modulating the balance between fibroblast proliferation and apoptosis.

Some circRNAs are profibrotic and their upregulation contributed to the development of keloids. Those profibrotic circRNAs include circCOL5A1、circ_0043688、circPDE7B、circ_101,238、circ_0008450、circNRIP1, and circ_0057452. However, some circRNAs are anti-fibrotic and their reduction inhibits the development of keloids. Those anti-fibrotic circRNAs include circSLC8A1 and circPTPN12. Gain- and loss-of-function studies have proven that deregulated circRNAs may regulate the processes underlying keloid formation and development.

CircRNAs are expected to be a potential diagnostic and therapeutic target in the management of keloids. For example, si-circCOL5A1 inhibited the growth and ECM deposition of keloids in the skin of nude mice (Lv et al., 2021). Further investigation into keloid-related circRNAs is needed to identify more effective prophylactic and clinical treatment strategies for keloids.