Signal Transduction and Targeted Therapy | Signaling Pathways, Therapeutic Targets, and Interventional Strategies in Ulcerative Colitis

Literature Overview

The article 'Ulcerative colitis: signaling pathways, therapeutic targets and interventional strategies,' published in the journal Signal Transduction and Targeted Therapy, reviews and summarizes the cellular processes, associated signaling pathways, and current treatment strategies in ulcerative colitis (UC). The paper systematically elaborates on the roles of key cellular processes—such as autophagy, endoplasmic reticulum stress, mitochondrial dysfunction, macrophage polarization, ferroptosis, and Th/Treg cell balance—in the development and progression of UC. It also deeply explores the regulatory mechanisms of signaling pathways including NF-κB, PI3K/AKT, Wnt/β-catenin, AMPK, TLR, JAK/STAT, lncRNA, and miRNA in UC. Additionally, the article summarizes various treatment approaches such as 5-aminosalicylate preparations, glucocorticoids, biologics, and fecal microbiota transplantation, emphasizing the future direction of multi-target precision therapy. The entire section is coherent and logically structured, ending with a Chinese period.

Background Knowledge

Ulcerative colitis (UC) is a chronic nonspecific inflammatory bowel disease that primarily affects the colonic mucosa, clinically characterized by abdominal pain, diarrhea, and mucopurulent bloody stool. The disease has a prolonged course, is prone to recurrence, and significantly increases the risk of colorectal cancer. Its pathogenesis is complex, involving the interaction of immune imbalance, intestinal barrier disruption, gut microbiota dysbiosis, and genetic susceptibility. Although multiple treatment options are currently available, there is no curative therapy, and some patients respond poorly to existing drugs, leaving unmet clinical needs. In recent years, with in-depth research into cellular processes such as autophagy, endoplasmic reticulum stress, and macrophage polarization, several key signaling pathways—including NF-κB, PI3K/AKT, and JAK/STAT—have been confirmed to participate in the inflammatory regulation of UC, making them potential therapeutic targets. Meanwhile, non-coding RNAs (such as miRNAs and lncRNAs), as novel regulatory molecules, also play important roles in UC and hold promise as diagnostic biomarkers or therapeutic intervention points. Furthermore, the gut microbiota, as a crucial hub for host-environment interactions, is closely linked to UC, and microbiota intervention strategies such as fecal microbiota transplantation have shown certain efficacy. However, how to achieve individualized and precise treatment and develop safer and more effective targeted drugs remains a key challenge in current research. This review systematically integrates the pathological mechanisms and therapeutic advances in UC, providing valuable references for future studies.

Research Methods and Experiments

This study is a systematic review that comprehensively summarizes the cell biological processes, key signaling pathways, and their molecular mechanisms in ulcerative colitis by integrating clinical and basic research literature published in recent years. The authors focus on analyzing the roles of cellular processes such as autophagy, endoplasmic reticulum stress, mitochondrial dysfunction, macrophage polarization, ferroptosis, and Th/Treg cell balance in the pathological progression of UC, and clarify the associated molecular mechanisms using evidence from experimental models (e.g., DSS-induced colitis mouse models, UC rat models). At the same time, the review systematically outlines the activation status, upstream and downstream regulatory factors, and the relationship with inflammatory responses and barrier function of classical signaling pathways in UC, including NF-κB, PI3K/AKT, Wnt/β-catenin, AMPK, TLR, and JAK/STAT. Additionally, the authors summarize the expression profiles and functions of various non-coding RNAs (e.g., miR-21, miR-155, lncRNA HOTAIR) in UC. The review also systematically summarizes current clinical treatment strategies, including 5-aminosalicylic acid, glucocorticoids, biologics, JAK inhibitors, and fecal microbiota transplantation, and discusses their mechanisms of action and limitations.

Key Conclusions and Perspectives

• Autophagy maintains intestinal epithelial homeostasis by clearing damaged proteins and organelles; its activation can alleviate UC inflammation and is a potential therapeutic target
• Endoplasmic reticulum stress is activated in UC patients, leading to protein misfolding and inflammatory responses; inhibiting this pathway can alleviate colonic injury
• Mitochondrial dysfunction triggers oxidative stress and disrupts the intestinal barrier; targeting mitophagy or antioxidant pathways holds therapeutic potential
• Imbalance in macrophage M1/M2 polarization promotes inflammatory progression; promoting M2 polarization or inhibiting M1 polarization can restore immune homeostasis
• The NF-κB pathway is a core driver of inflammation in UC; numerous natural compounds and clinical drugs exert therapeutic effects by inhibiting this pathway
• The PI3K/AKT pathway regulates cell proliferation and immune responses; its abnormal activation contributes to UC progression and is an important intervention target
• Gut microbiota dysbiosis leads to a reduction in beneficial bacteria and an increase in pathogenic bacteria, affecting immune regulation and barrier function; microbiota intervention strategies such as FMT have promising applications
• Non-coding RNAs (e.g., miRNAs, lncRNAs) are differentially expressed in UC and participate in inflammatory regulation, serving as potential diagnostic biomarkers or therapeutic targets
• Although current treatments such as 5-ASA, steroids, and biologics are effective, they suffer from suboptimal response rates or side effects, highlighting the urgent need for more precise therapies
• Future research should focus on multi-target synergistic interventions and the development of personalized treatment strategies to achieve precision medicine in UC

Research Significance and Prospects

This review systematically integrates the pathological mechanisms and treatment advances in UC, providing a comprehensive perspective for understanding disease progression. By summarizing multiple key cellular processes and signaling pathways, it identifies potential therapeutic targets and offers theoretical support for novel drug development. In particular, the summary of emerging fields such as autophagy, macrophage polarization, and gut microbiota expands the thinking for therapeutic interventions.

Looking ahead, molecular subtyping based on multi-omics data will help achieve individualized treatment. Novel strategies such as small-molecule inhibitors targeting specific signaling pathways, live biotherapeutic products modulating gut microbiota, and oligonucleotide therapies based on non-coding RNAs warrant further exploration. In addition, combining AI-assisted drug design with animal model validation is expected to accelerate the development of targeted therapies. The ultimate goal is to achieve precise diagnosis and long-term remission in UC, thereby improving patients' quality of life.

Conclusion

This article systematically summarizes the cellular mechanisms, key signaling pathways, and treatment strategies in ulcerative colitis, emphasizing the central roles of cellular processes such as autophagy, endoplasmic reticulum stress, macrophage polarization, and gut microbiota dysbiosis in disease progression. Signaling pathways such as NF-κB, PI3K/AKT, and JAK/STAT have been widely confirmed to participate in inflammatory regulation and are important targets for current drug development. Although existing treatments such as 5-aminosalicylic acid and biologics have improved outcomes for some patients, unmet clinical needs remain. The discovery of non-coding RNAs provides new directions for the diagnosis and treatment of UC. Future research should focus on developing multi-target synergistic interventions and personalized treatment strategies. By integrating molecular subtyping, precise animal models, and novel drug screening platforms, more effective disease control may be achieved. This review provides a comprehensive theoretical foundation for researchers and points the way for clinical translational research. Advancing from empirical treatment to precision medicine is the key path toward achieving functional cures in UC.