Facts

  • p53 plays a crucial but complicated role in regulating organ fibrosis.

  • p53-mediated cell senescence and apoptosis are required for organ fibrosis.

  • The crosstalk between p53 and multiple cells regulates organ fibrosis.

Open Question

  • How p53 regulates the balance between cell proliferation and senescence in the course of organ fibrosis?

  • Why the protein level and activity of p53 are differentially controlled in a cell type-specific manner during organ fibrosis?

  • What are the potential problems and challenges for targeting p53 in treatment of organ fibrosis?

Introduction

Fibrosis is a pathological scarring process characterized primarily by chronic inflammation, excessive extracellular matrix (ECM) deposition, and activation of myofibroblasts [1]. Damage to tissues can result from various factors, including aging, inflammation, toxins, and infections. Following persistent tissue injury, the epithelium and endothelium trigger the release of inflammatory and immune mediators as part of the wound healing programs [2]. Activated fibroblasts and myofibroblasts are the crucial cellular effectors of fibrotic disease. Shortly after an initial inflammatory phase, quiescent resident fibroblasts transform into myofibroblasts, which significantly increase the production of ECM in damaged tissues [3]. When chronic injury and inflammation persist, ongoing wound-healing responses can evoke unrestrained tissue damage, repair, and regeneration, eventually leading to fibrosis in different organs such as kidney, liver, lung, and heart. (Fig. 1). Fibrotic remodeling is implicated in numerous diseases, including scleroderma, myocardial infarction, heart failure, cystic fibrosis, idiopathic pulmonary fibrosis (IPF), chronic kidney disease (CKD), diabetes, non-alcoholic steatohepatitis, and hepatitis, often resulting in organ dysfunction, failure, and even death [4]. Organ transplantation remain the only effective therapeutic option for end-stage diseases, unfortunately, donor organs are often in short supply. Despite extensive research on organ fibrosis, its pathogenesis has not been fully explained and the effective therapies are still lacking.

Fig. 1: Schematic illustration of fibrosis pathogenesis in different organs.
figure 1

Noxious stimuli result in organ damage, inflammation, and fibrosis in the kidney, liver, lung, and heart. Fibrotic remodeling is implicated in numerous diseases and closely related to epithelial-mesenchymal transition (EMT), cell apoptosis, and cell senescence. Multiple functioning cells in different organs can be activated into myofibroblasts and further deposit large amounts of extracellular matrix, eventually leading to the formation of fibrosis.

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The tumor suppressor p53 (p53) is a member of sequence-specific nuclear transcription factors family, which includes two other members p73 and p63. Primitively, p53 is regarded as a type of tumor suppressor gene in the body that participates in the regulation of cell cycle arrest, apoptosis, senescence, ferroptosis, and autophagy to promote cell survival or limit cell malignant transformation [5]. It has been shown that p53 can modulate dynamin-related protein 1 mediated mitochondrial dynamics or directly activate the cellular senescence regulator p21 to accelerate cell cycle arrest and cell senescence [6, 7]. The B cell lymphoma-2 (Bcl-2) family proteins, including BAX, p53-upregulated modulator of apoptosis (PUMA), and NOXA, are key regulators for p53-dependent apoptosis checkpoints. Additionally, p21 and GADD45A have emerged as potent downstream mediators for p53-dependent cell cycle arrest [8]. The incidence of apoptosis is raised among most types of aging cells in the body [9]. Cell senescence and apoptosis have emerged as crucial predisposing factors for organ fibrosis [10, 11]. Numerous studies have demonstrated that p53 serves as master regulator of apoptosis and senescence, exerts regulating effects on fibroblast activation and ECM production, indicating that p53 plays a crucial role in the development of organs fibrosis.

In this review, we will focus on recent advances of p53 on organ fibrosis. Firstly, we will introduce the structure and function of p53, and then illustrate the underlying pathological mechanisms of organ fibrosis. In addition, we will discuss potential directions of p53-targeted therapy for fibrosis in different organs, which may provide potential ideas for the diagnosis and treatment of fibrotic diseases.

p53

Structure and function

The p53 gene contains multiple functional structural domains such as an N-terminal transactivation domain (TAD1 and TAD2, residues 1-40 and 40-60, respectively), a proline-rich domain (PRD, residues 60-90), a DNA-binding domain (DBD, residues 94-312), a C-terminal oligomerization domain (OD, residues 323-355), as well as a C-terminal domain (CTD, residues 364-393). Typically, the promoter response element DNA binding by p53 is an essential early step for transcriptional activation [12]. TAD1 and TAD2 involve several phosphorylation sites, which can modulate degradation and activity of p53 in response to stress stimulus [13]. In addition, the inactivation of TAD1 and TAD2 has been shown to play a role in directing p53 target gene selection, suppressing the growth of tumor, and promoting cellular senescence [14, 15]. Mutations or deletions in the PRD can regulate p53 degradation, transactivation function, and growth suppression [16, 17]. The following DBD is required for the definition of primary DNA-binding specificity. Besides, it can also carry numerous hot-spot mutation sites to control tumor suppressive transcription factor activity [18, 19]. Notably, CTD is highly unstructured and harbors primary sites for acetylation, methylation, and phosphorylation. These modifications are directly involved in p53 functions regulation in all aspects, such as transcriptional activity, protein stability regulation, co-factors recruitment, and complex DNA-binding behavior [20, 21].

Activation mechanism

The p53 is activated in response to a range of stimuli, including DNA damage, hypoxia, oncogene activation, and ribosomal stress. The activation involves a three-step sequential process, which includes p53 stabilization, derepression, and promoter-specific activation [22]. Many mechanisms such as genetic (mutation, single-nucleotide polymorphism), transcriptional (epigenetic inhibition of p53 transcription), mRNA (alternative splicing), and protein (protein folding, localization)-level regulation, have been shown to regulate p53 activation and its function [5]. Notably, post-translational modifications (PTMs) can regulate p53 stability, conformation, localization, binding partners and are the most important mechanism to modulate p53 levels and activity [23]. There are more than 300 different PTMs of p53, mainly include acetylation, phosphorylation, methylation, and ubiquitination. It has been confirmed that TIP60 acetyltransferase mediates p53 acetylation at K120, which is required for p53-dependent cell growth arrest and apoptosis [24, 25]. Hepatocyte odd protein shuttling is a novel shuttling protein that facilitates p53-dependent mitochondrial apoptosis by inhibiting the proteasomal degradation of p53 [26]. The E3 ubiquitin ligase murine double minute 2 (MDM2) and its homolog murine double minute 4 (MDM4) are the two primary negative regulators of p53, which play essential roles in ferroptosis, DNA repair, and senescence regulation [27, 28]. MDM2 not only promotes ubiquitylation and proteasomal-dependent degradation of p53, but also binds to p53 to directly inhibit its transcriptional activity [29]. N‐acetyltransferase 10 promotes p53 activation by acetylating p53 at K120 and counteracting MDM2 action [30]. The phosphorylation of p53 on S15, T18, and S20 residues disrupts the binding of p53-MDM2, leading to aberrant p53 regulation and aging phenotypes [31, 32]. In addition, MDM4 has been shown to interact with MDM2 to reverse MDM2-mediated p53 degradation while maintain suppression of p53 transactivation [33].

Pathogenesis of fibrosis

Fibrosis is a progressive medical condition and an outcome of severe tissue damage or wound healing disorders. The pathological mechanisms underlying fibrosis in various organs primarily encompass epithelial-mesenchymal transition (EMT), cell apoptosis, and cell senescence.

EMT

There are several basic types of epithelial cells such as secretory, ciliated, club, goblet, and basal cells, which are crucial to maintain tissue homeostasis in various organs [34]. During fibrotic process, organs are exposed to chronic and continuous stimuli, epithelial cells can undergo a great diversity of changes in response to injury. Damaged cells dedifferentiate into mesenchymal states (EMT), which accompanied by the loss of apical-basal polarity and adhesion [67, 1). Secondly, the precise upstream regulators and downstream target genes of p53 during organ fibrosis have yet to be fully explored. The diversity and specificity of p53’s functions pose significant challenges in elucidating the regulatory mechanisms of p53 in organ fibrosis, as well as in develo** relevant drug prevention and treatment programs. Consequently, further research should prioritize addressing these aforementioned problems to expedite the development of novel and promising therapeutic drugs that target p53 for the treatment of organ fibrosis.

Table 1 Summary of the p53 involved in organ fibrosis.
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