Due to various reasons, skin surface injuries occur frequently [9] . During the process of tissue damage, there is a common response to the injury, including several overlapping events, known as wound healing. Wound healing is a dynamic process involving many cellular participants and structures, and these cellular and molecular events are highly coordinated and controlled [10] . Normal wound healing is divided into three stages: the inflammatory phase, the proliferative/granulation phase, and the maturation/remodeling phase. After skin injury, inflammation first occurs in the local tissue [11] . The inflammatory process begins with tissue damage, which activates platelets, neutrophils, and macrophages, prompting them to release inflammatory mediators and cytokines, thereby participating in the recruitment of inflammatory cells, fibroblasts, endothelial cells, and epithelial cells. The subsequent proliferative stage is characterized by the activation of fibroblasts, the differentiation of myofibroblasts, and the accumulation and deposition of extracellular matrix (ECM). The third healing stage is matrix remodeling, including scar tissue remodeling [12] . In the early stage of repair, inflammatory cells exert pro-inflammatory effects through cytokines. Usually, the repair and healing stage begins after 72 hours, and collagen remodeling is ultimately completed [13] . Studies have shown that chronic inflammatory responses are associated with scar formation [14] . Inflammation is involved in the regulation of collagen synthesis. However, excessive inflammatory responses can lead to an imbalance between the synthesis and degradation of extracellular matrix, thereby forming pathological scars. The intensity of inflammation is positively correlated with the size of the final scar.

The inflammatory phase is the initial stage of wound healing, and the inflammatory response plays a crucial regulatory role in the outcome of wound healing. Excessive and intense inflammation leads to the infiltration of inflammatory cells into the wound site, generating a series of inflammatory cytokines, including interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α). These factors, in turn, promote fibroblast proliferation and excessive collagen secretion, thereby facilitating the formation of hypertrophic scars (HSs) [15] .

Approximately two hours after skin tissue damage, neutrophils are guided to the injury site by inflammatory signals released by platelets and the resident immune cell population in the tissue (including macrophages, dendritic cells, and mast cells) to respond. Resident immune cells in the tissue are mature innate immune cells that develop in the surrounding tissue and remain throughout their lifetime [16] . Resident immune cells secrete various chemokines that promote neutrophil recruitment and chemotaxis, i.e. migration to the wound site. Neutrophils are among the first inflammatory cells to arrive at the injury site. They play a key role in clearing debris and preventing infection by releasing reactive oxygen species, proteases, antimicrobial peptides, and neutrophil extracellular traps (NETs), and by phagocytosing and killing pathogens [17] . Mast cell-derived mediators enhance the expression of factor XIIIa in dermal dendritic cells by releasing TNF-α, which helps with hemostasis and clot formation and stabilizes the clot. Keratinocytes recruit mast cells to the site by secreting stem cell factor (SCF). Mast cells then release a series of inflammatory mediators, including histamine, vascular endothelial growth factor (VEGF), IL-6, and IL-8, which play a crucial role in increasing endothelial cell permeability and promoting vasodilation, and effectively induce the directional migration of inflammatory cells, especially monocytes and neutrophils, to the damaged area. Mast cells can activate fibroblasts and keratinocytes, which are the main cells involved in wound healing. During the proliferation stage, mast cells promote the division and proliferation of fibroblasts through the action of IL-4, vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF), thereby generating new extracellular matrix (ECM) components. Mast cell-derived mediators, including fibroblast growth factor-2, VEGF, platelet-derived growth factor (PDGF), TGF-β, nerve growth factor (NGF), IL-4, and IL-8, contribute to angiogenesis, fibrogenesis, or re-epithelialization during the repair process [18] . The primary source of wound-associated macrophages is the circulating monocyte pool in the blood, which enters the injury site through vascular leakage, while skin-resident macrophages are a secondary source. At the injury site, resident macrophages polarize to an inflammatory phenotype, sometimes referred to as the M1 phenotype, in response to local pathogens, necrotic tissue residues, and various factors such as IFN-γ derived from natural killer cells. M1 macrophages secrete pro-inflammatory factors such as IL-1β, IL-6, IL-12, IL-23, and TNF-α, further stimulating monocyte infiltration. Secreted IL-1 increases collagen synthesis and promotes the proliferation of fibroblasts and keratinocytes [19] . Factors such as IL-1β, IL-6, IL-12, IL-23, and TNF-α not only activate immune cells but also promote the proliferation and differentiation of fibroblasts and induce the synthesis of extracellular matrix. At the same time, their complex interactions further intensify the intensity and persistence of the inflammatory response.

During the inflammatory phase, inflammatory cells release various growth factors that serve as core regulatory elements in tissue repair. These polypeptides, secreted by activated cells in the injured area, promote cell division and recruit new cells to the wound site. Among them, platelet-derived growth factor (PDGF) is rapidly released from damaged platelet α-granules, attracting neutrophils, macrophages, and fibroblasts while acting as a potent mitogen [20] . PDGF enhances fibroblast proliferation and migration via the PI3K/AKT/mTOR pathway and induces VEGF expression, synergistically promoting scar vascularization (studies show PDGF receptor inhibitors reduce scar thickness). Platelets also release TGF-β, a key cytokine with diverse roles in wound healing and fibrosis. TGF-β1 synergizes with PDGF by upregulating PDGF receptor expression, amplifying fibroblast sensitivity to PDGF. VEGF interacts with inflammatory factors: IL-6 stimulates VEGF secretion via the STAT3 pathway, forming an “inflammation-angiogenesis-fibrosis” axis. VEGF family members are critical regulators of tissue repair but may also promote inflammation and scarring depending on receptor-specific activation. Over the past decade, evidence has highlighted VEGF’s pivotal role in scar formation, with elevated levels linked to normal scars, hypertrophic scars, and keloids. Experimental studies demonstrate that VEGF inhibition reduces scar tissue deposition. Notably, VEGFR-2 activation accelerates skin healing, while VEGFR-1/VEGFR-3 activation may drive inflammation and fibrosis. Selective VEGFR-2 stimulation via viral VEGF-E enhances IL-10 expression, reduces macrophage infiltration and myofibroblast differentiation, improves microvascular density, and promotes pericyte coverage in healed wounds. Epidermal growth factor (EGF), another key peptide, coordinates cell growth, proliferation, and differentiation during healing. Recombinant human EGF (rhEGF) is widely used to accelerate repair by stimulating epithelialization, shortening the inflammatory phase, and promoting organized collagen remodeling, thereby reducing fibrosis [21] .

The primary characteristics of skin scar formation include persistent activation of myofibroblasts and excessive extracellular matrix (ECM) deposition. The exact mechanisms underlying scar formation remain unclear. However, fibroblasts are considered key cells involved in scar formation, as their abnormal proliferation and excessive collagen deposition often lead to scarring. ECM remodeling is mediated by myofibroblasts, which are differentiated fibroblasts [22] . Studies indicate that myofibroblasts exhibit robust ECM-secreting capabilities and represent an activated form of resident wound tissue fibroblasts. As the most critical effector cells associated with scar formation, myofibroblasts are typically activated during inflammatory responses.

Cytokines such as IGF-1, HIF-1, PDGF, and TGF-β play vital regulatory roles in fibroblast proliferation and differentiation. They influence the synthesis and degradation of the extracellular matrix by modulating fibroblast signaling pathways and gene expression. During pathological scar formation, hyperdifferentiated myofibroblasts exhibit uncontrolled ECM production, secrete cytokines, and become hypersensitive even to low concentrations of growth factors. Overdifferentiated keratinocytes produce fibrotic factors, including vascular endothelial growth factor, epidermal growth factor, connective tissue growth factor, insulin-like growth factor 1, and excessive TGF-β, which promote fibrosis through fibroblast hyperproliferation and collagen overproduction at wound sites. Dysregulation of TGF-β superfamily members, such as activin, also contributes to chronic wound healing and excessive scarring. Activin promotes wound healing by stimulating granulation tissue formation and keratinocyte proliferation [22] . Cytokine networks and signaling pathways exhibit cross-regulation: for example, TGF-β1 induces IL-6 expression, while IL-6 enhances TGF-β receptor stability via STAT3, forming a positive feedback loop. Combined local delivery of TGF-β inhibitors and IL-10 synergistically inhibits fibrosis and promotes tissue remodeling. Additionally, IL-10 significantly suppresses keloid fibroblast proliferation and differentiation by inhibiting the TGF-β/Smad signaling pathway, consistent with findings from previous studies by Shi et al. [23] .

Oxidative stress arises from the generation of oxygen- and nitrogen-based free radicals and the imbalance in cellular antioxidant mechanisms. This state is driven and mediated by free radicals released through physiological aerobic metabolic pathways and pathological inflammatory responses. Free radicals include reactive oxygen species (ROS) and reactive nitrogen species (RNS), with ROS encompassing superoxide anions ( ${\text{O}}_2^{-}$), peroxides, hydroxyl radicals (HO∙), and singlet oxygen (¹O₂) [24] . In the body, when ROS production exceeds normal levels or antioxidant defense mechanisms weaken, significant accumulation of ROS and its derivatives occurs. This state poses toxic threats to cellular structures and tissue functions, constituting a pathological condition. NAD⁺ and NADH act as coenzymes, providing redox capacity for mitochondrial ATP generation. NAD⁺ serves as the precursor for NADP and NADPH, which protect cells from ROS damage. Conversely, NADPH oxidase 2 (NOX2) catalyzes molecular oxygen to generate superoxide, a major source of cellular ROS. Excessive ROS production leads to intracellular oxidative stress and inflammation [25] .

In keloid tissues, the TGF-β1/SMAD signaling pathway is significantly activated, accelerating the progression of dermal fibrosis. Elevated ROS levels have been observed in keloid fibroblasts. Specifically, TGF-β1 enhances the fibrotic characteristics of fibroblasts and promotes the expression of early growth response factor 1 (EGR1) through precise regulation of the SMAD signaling pathway in keloids. EGR1 plays a critical role by directly targeting NADPH oxidase 4 (NOX4), effectively regulating ROS generation. Furthermore, NOX4-derived ROS promotes the fibrotic-like phenotype of keloid fibroblasts and plays a key role in keloid fibrosis [26] . Under oxidative stress, miR-21 (pro-fibrotic) is upregulated, while miR-29 (anti-fibrotic) is downregulated, exacerbating extracellular matrix (ECM) deposition. ROS also activates multiple signaling pathways: for example, ROS triggers ERK, JNK, and p38 MAPK pathways to induce fibroblast proliferation, while simultaneously upregulating pro-inflammatory factors (IL-6, TNF-α) via NF-κB, forming an inflammation-fibrosis positive feedback loop. This process induces the expression and release of inflammatory factors. Concurrently, inflammatory factors further promote ROS production and accumulation, creating a vicious cycle. Such interactions exacerbate scar formation and progression.

MicroRNAs (miRNAs) are small, endogenous, non-coding single-stranded RNA molecules composed of 18 - 22 nucleotides (nt). They post-transcriptionally regulate gene expression by directly binding to the 3’ untranslated region (UTR) of target mRNAs [27] . Numerous types of non-coding RNAs have been identified, which are abundant and capable of modulating gene expression. These include transfer RNAs (tRNAs), ribosomal RNAs (rRNAs), small RNAs such as microRNAs (miRNAs) and small interfering RNAs (siRNAs), as well as long non-coding RNAs (lncRNAs). Recent studies have revealed distinct expression levels of miRNAs and lncRNAs in keloid tissues and keloid-derived fibroblasts compared to normal tissues and fibroblasts, suggesting that non-coding RNAs may play a role in the pathogenesis of keloids [28] .

In recent years, research on miRNAs has grown significantly, spanning fields from tissue repair to targeted cancer therapies. This study demonstrates that miR-152-5p expression is markedly reduced in keloid tissues and their constituent cells. Through regulatory mechanisms, this miRNA inhibits Smad3 expression in keloids, thereby suppressing cell proliferation and migration while promoting apoptosis. MiR-152-5p may exert anti-fibrotic effects in keloids by modulating Smad3-mediated activation of Erk1/2 and Akt [29] . Similarly, miR-182-5p inhibits fibrosis and scar formation in hypertrophic fibroblasts (HFs) via the SMAD4 pathway, with its anti-scarring effects potentially linked to the regulation of proliferation, apoptosis, and migration [30] . Overexpression of miR-149 in HaCaT cells downregulates the expression of pro-inflammatory cytokines IL-1α, IL-1β, and IL-6 under both basal and inflammatory conditions. Furthermore, miR-149 indirectly enhances the expression of transforming growth factor-β3 (TGF-β3) and type III collagen in fibroblasts, which are essential for extracellular matrix remodeling [31] . TGF-β1, which is upregulated in keloid tissues, promotes the proliferation, collagen production, and differentiation of dermal fibroblasts. During keloid formation, the interaction between TGF-β1 and miR-21 plays a central role in regulating FasL protein. Concurrently, activation of the PTEN/AKT signaling pathway and upregulation of miR-21 collectively contribute to TGF-β1-mediated proliferation and transdifferentiation of keloid fibroblasts (KFs). Inhibition of miR-21 expression effectively reduces KF proliferation and impedes transdifferentiation, suggesting that miR-21 may serve as a therapeutic target for keloids. Additionally, another study found that miR-21 promotes collagen production in keloids by negatively regulating Smad7 [32] . These findings provide novel insights into the potential application of miRNAs in the prevention and treatment of pathological scarring.