Multiple roles of p53 in cancer development: Regulation of tumor microenvironment, m⁶A modification and diverse cell death mechanisms

Graphical abstract

Highlights

• •Multifaceted Role of p53 in Cancer: Investigating p53’s functions in cancer biology and its impact on tumor progression and treatment.
• •Interactions in the Tumor Microenvironment: Examining p53’s role with various cell types and pathways in the TME affecting cancer.
• •p53 and m6A Modification: Exploring the link between p53 and m6A RNA modification and its implications for cancer.
• •p53 Regulation of Cell Death Mechanisms: Identifying p53’s role in autophagy, ferroptosis, and other cell death pathways.
• •Therapeutic Implications: Exploring potential targets based on p53’s roles and contributions to personalized cancer treatments.

Abstract

Background

The protein p53, encoded by the most frequently mutated gene TP53 in human cancers, has diverse functions in tumor suppression. As a best known transcription factor, p53 can regulate various fundamental cellular responses, ranging from the cell-cycle arrest, DNA repair, senescence to the programmed cell death (PCD), which includes autophagy, apoptosis, ferroptosis, cuproptosis, pyroptosis and disulfidoptosis. Accumulating evidence has indicated that the tumor microenvironment (TME), N⁶-methyladenosine (m⁶A) modification and diverse PCD are important for the progression, proliferation and metastases of cancers.

Aim of review

This paper aims to systematically and comprehensively summarize the multiple roles of p53 in the development of cancers from the regulation of TME, m⁶A Modification and diverse PCD.

Key scientific concepts of review

TME, a crucial local homeostasis environment, influences every step of tumorigenesis and metastasis. m⁶A, the most prevalent and abundant endogenous modification in eukaryotic RNAs, plays an essential role in various biological processes, containing the progression of cancers. Additionally, PCD is an evolutionarily conserved mechanism of cell suicide and a common process in living organisms. Some forms of PCD contribute to the occurrence and development of cancer. However, the complex roles of p53 within the TME, m⁶A modification and diverse PCD mechanisms are still not completely understood. Presently, the function roles of p53 including the wild-type and mutant p53 in different context are summarized. Additionally, the interaction between the cancer immunity, cancer cell death and RNA m⁶A methylation and the p53 regulation during the development and progress of cancers were discussed. Moreover, the key molecular mechanisms by which p53 participates in the regulation of TME, m⁶A and diverse PCD are also explored. All the findings will facilitate the development of novel therapeutic approaches.

Introduction

Cancer, a disease characterized by uncontrolled cell division, remains a major global health issue, causing millions of deaths annually [1]. Despite significant advances in cancer research, its incidence continues to rise, highlighting the critical need for more effective prevention and therapeutic approaches. In recent years, research has increasingly focused on elucidating the molecular mechanisms driving cancer development, with particular attention to identifying key genetic contributors to tumorigenesis [1]. Among these, the p53 protein, encoded by the TP53 gene, has emerged as a pivotal regulator of cellular homeostasis and a potent tumor suppressor [2]. Since its discovery in 1979, p53 has garnered extensive attention for its essential role in maintaining genomic stability and preventing the onset of cancer [3].

Actually, numerous studies have emphasized the pivotal role of p53 in tumor suppression, with its dysfunction implicated in a broad spectrum of cancers [4]. Notably, mutations in the TP53 gene are observed in over 50 % of human tumors, highlighting the important role of p53 in cancer biology [5]. Despite extensive research, key questions remain, particularly regarding the specific mechanisms by which p53 exerts its tumor-suppressive effects [6]. Moreover, the development of drug resistance continues to challenge the effectiveness of conventional cancer therapies, underscoring the need for alternative treatment strategies that target the complex interactions between tumor cells and their microenvironment [7].

In addition, the tumor microenvironment (TME) is a critical local homeostatic niche that influences every stage of tumorigenesis and metastasis [8]. Moreover, N6-methyladenosine (m⁶A), the most prevalent endogenous modification in eukaryotic RNAs, plays a pivotal role in various biological processes, including cancer progression [9]. Besides, the programmed cell death (PCD), an evolutionarily conserved mechanism of cellular suicide, also contributes to the occurrence and progression of cancer [10]. However, the intricate roles of p53 within the TME, m⁶A modification, and diverse PCD pathways remain incompletely understood.

Presently, the paper is the first comprehensive summary of the functions of wild-type and mutant p53 in different contexts (Fig. 1). Additionally, we also explores the interactions between cancer immunity, cancer cell death, RNA m⁶A methylation, and p53 regulation during cancer development. Moreover, the crucial molecular mechanisms by which p53 regulates the TME, m⁶A, and multiple PCD forms are discussed. All the findings will offer novel insights into targeting p53 for cancer therapy and propose avenues for developing personalized treatment strategies tailored to individual patients.

Fig. 1.

p53 regulates tumors by modulating the tumor microenvironment (TME), autophagy, ferroptosis, cuproptosis, pyroptosis, endoplasmic reticulum (ER) stress, and disulfidoptosis, as well as key genes and pathways in m⁶A modification.

The tumor microenvironment

Understanding the tumor microenvironment (TME)

The TME is a complex ecosystem comprising various cellular components, including endothelial cells, immune cells, and fibroblasts [11]. Endothelial cells play a critical role in tumor progression by promoting angiogenesis, which supplies tumors with essential nutrients while simultaneously forming a physical barrier that shields tumor cells from immune surveillance [12]. Additionally, immune cells, comprising granulocytes, lymphocytes, and notably macrophages, are indispensable constituents of the TME, orchestrating a spectrum of immune responses crucial for tumor survival [13]. Among these, macrophages are particularly prominent, performing diverse functions related to cancer initiation and progression, including facilitating tumor cell intravasation into the bloodstream and suppressing anti-tumor immune responses [11]. Accumulating evidence highlights the central role of tumor-associated macrophages (TAMs) in influencing the efficacy of anti-tumor therapies, such as radiotherapy, cytotoxic drugs, and immune checkpoint inhibitors [14].

In addition, cancer-associated fibroblasts (CAFs) as one of the most abundant matrix components in TME, are a collection of multiple cell subsets that can respond to different matrix stimuli, exhibit different subpopulations with either tumour- promoting or tumour-suppressive effects in different systems [15]. Actually, specific markers in cell surface determine the type of CAF subgroup, which in turn determines its function. For example, the CXCL12/CXCR4 cascade in FAP + CAFs can promote the cell proliferation cancer [16]. Additionally, studies also have shown that CAFs promote tumor angiogenesis through VEGF-dependent and VEGF-independent pathways [17]. Moreover, angiogenesis-regulating factors produced by CAFs, such as VEGFA, PDGFC, FGF2, CXCL12, osteopontin and CSF3, promote the growth of tumor-associated vasculature by recruiting myeloid cells, and accelerate tumor angiogenesis by attracting vascular endothelial cells and recruiting monocytes [18]. Besides, CAFs also exert pro-tumorigenic functions by influencing tumor metastasis. For instance, in breast cancer, different amounts of S1 CAFs and S4 CAFs were found in metastatic axillary lymph nodes, driving tumor cell migration and invasion through the CXCL12, TGFβ, and NOTCH signaling pathways, respectively [19], [20]. Additionally, myoCAF initiates PDAC metastasis through the IL-33-ST2-CXCL3-CXCR2 axis [21], [22].

With respect to the tumour-suppressive effects of CAFs, recent studies indicate that CAFs can significantly enhance drug sensitivity, thereby exerting anti-tumor effects [23]. For instance, in lung cancer, a distinct subset of cancer-associated fibroblasts (CAFs), characterized by CD200 expression, has been shown to enhance the sensitivity of cancer cells to the epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) gefitinib [23]. However, this sensitizing effect is abrogated upon CD200 gene knockout, highlighting the critical role of CD200-positive CAFs in modulating therapeutic response [23]. Additionally, in a study of pancreatic ductal adenocarcinoma (PDAC), the depletion of αSMA + myofibroblastic cancer-associated fibroblasts (myCAFs) has been linked to heightened immunosuppression and decreased overall survival [24]. Notably, myCAFs exert tumor-suppressive effects, in part, via the SHH-SMO signaling pathway [29], [30]. Moreover, Type I collagen, produced by myCAFs, plays a crucial role in constraining the growth of desmoplastic tumors [25]. In mouse models, the deletion of type I collagen significantly enhances metastasis in both PDAC and colorectal cancer (CRC), suggesting that type I collagen creates a mechanical barrier that limits tumor expansion [25]. Furthermore, IL-8 secreted by CAFs inhibits the proliferation of OCUCh-LM1 cell lines, which are associated with tumorigenesis [26], [27]. Fig. 2 depicts the role of p53 in the tumor microenvironment by inhibiting angiogenesis, suppressing fibroblast cells, Treg cell generation.

Fig. 2.

p53 plays a role in the tumor microenvironment by inhibiting angiogenesis, suppressing fibroblast cells, Treg cell generation, promoting macrophage cells, and facilitating T cell infiltration to suppress tumors.

The regulation of tumor microenvironment and immune response by p53

Inflammation and tissue remodeling are key characteristics of the TME, crucial for the dissemination, proliferation and maintenance of cancer stem cells (CSCs) [28]. Indeed, the role of p53 in regulating the immune response within TME has attracted considerable attention. Emerging evidence supports the function of p53 as a tumor suppressor in the inflammatory environment, reducing the inflammatory response [28]. Its absence often leads to increased inflammation, chronic immunosuppression and tumor progression [29]. For example, inactivation of p53 hampers effective immune-mediated tumor clearance, while reactivation or restoration of p53 in the TME can alter the immune landscape, counteracting immunosuppression and promoting antitumor immunity [30].

Additionally, activation of p53 initiates apoptosis in tumor cells and activates immune cells, thereby facilitating tumor antigen presentation and immune cell recognition, consequently amplifying immune-mediated tumor clearance [31]. Moreover, p53 activation reduces the activity of immunosuppressive components within the TME, including regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs) and programmed death-ligand 1 (PD-L1), thereby mitigating immune evasion [32]. Actually, recent investigations underscore the impact of p53 deficiency within the TME on immunotherapy and other anti-tumor modalities [33]. For instance, p53 deficiency correlates with resistance to immune checkpoint inhibitors, which constitute a cornerstone of immunotherapy aimed at blocking suppressive signals in T cells and bolstering anti-tumor immunity [34]. Furthermore, perturbations in the TME conducive to tumor cell survival and resistance to chemotherapy and radiation may stem from p53 dysregulation [35].

In addition to its immunomodulatory role, p53 exerts influence over the composition and architecture of the TME. By regulating angiogenesis within the TME, p53 acts as a barrier to tumor initiation and progression [36]. Through regulation of angiogenesis-associated gene expression, p53 inhibits the formation of new blood vessels within the TME, thereby limiting the supply of nutrients and oxygen to the tumor [36]. In contrast, the loss of functional p53 promotes unchecked angiogenesis, facilitating the continuous delivery of essential nutrients and oxygen to tumor cells, thus driving tumor growth and progression [36]. Furthermore, p53 deletion may influence the extracellular matrix by modulating its degradation and remodeling, thereby enhancing tumor invasion and metastasis [37].

N⁶-Methyladenosine (m⁶A) modification

The key role of m⁶A modification in RNA biology

m⁶A represents the most common and abundant cooperative transcriptional alteration in eukaryotic RNA, particularly in more developed eukaryotic cells [38]. This modification plays a pivotal role as a posttranscriptional regulatory marker in various RNA forms, including circular RNAs (circRNAs), long noncoding RNAs (lncRNAs), messenger RNAs (mRNAs), ribosomal RNAs (rRNAs), and transfer RNAs (tRNAs) [39]. Moreover, m⁶A modification governs crucial aspects of RNA biology, including translation, splicing, translocation, stability, and complex formation [40], thereby implicating almost every RNA species. Notably, the Drach motif harbors the majority of m⁶A loci [41]. Installation of m⁶A is orchestrated by a methyltransferase ensemble known as the m⁶A writer, comprising METTL3, METTL14, METTL16, ZC3H13, KIAA1429, WTAP, and RBM15 [42], while removal of the methyl group at position 6 of adenosine is facilitated by demethylases, also referred to as m⁶A erasers, such as FTO and ALKBH5[43]. Furthermore, proteins designated as m⁶A readers discern RNAs bearing m⁶A alterations, with an array of these proteins identified, including IGF2BP1/2/3, YTHDC1, YTHDF2, YTHDF3, YTHDC1, HNRNPA2B1 and HNRNPC [44]. Actually, studies have elucidated the involvement of m⁶A RNA methylation regulatory factors in various human disorders, notably heart failure, azoospermia, non-alcoholic fatty liver disease, and, significantly, human cancer [45].

The impact of m⁶A modification on p53 and its role in cancer

The influence of m⁶A modification extends to the translation and stability of p53, thereby modulating its expression level and function (Fig. 3). Research has underscored the pivotal role of m⁶A in controlling colorectal cancer (CRC) cell motility, invasion, and apoptosis, with p53 emerging as indispensable for m⁶A 's regulatory function in CRC progression [46]. Specifically, m⁶A governs the stability of p53 mRNA, thereby dictating CRC's malignant biological behavior [46]. Additionally, m⁶A mutations may impact post-translational modifications such as phosphorylation and ubiquitination, further modulating the stability and functionality of p53. Moreover, m⁶A modification can influence the expression of downstream genes regulated by p53, including Myc, CEBPA, and PTEN, thereby impacting apoptosis and cell proliferation [47]. Besides, perturbations in m⁶A may also exert control over cancer cell growth, programmed cell death, and invasion through modulation of the p53 signaling pathway [48]. Furthermore, m⁶A modification can influence the interaction between the p53 signaling pathway and other signaling cascades thus impinging upon tumor cell behavior [48].

Fig. 3.

Mettl3 methylates p53 mRNA, inhibiting p53-mediated apoptosis and cell cycle arrest, thereby reducing its stability and transcriptional activity, while p53 impedes METTL3 expression, decreasing m⁶A modification and promoting SOCS2 expression, ultimately restraining tumor development. Additionally, p53 modulates the expression and activity of the m⁶A binding protein YTHDF2, influencing mRNA degradation and translation, and stimulates ALKBH5 transcription, establishing a feedback loop to regulate m⁶A modification.

Regulatory role of p53 in m⁶A RNA methylation

M⁶A methylation plays a crucial role in regulating both the mRNA and protein stability of p53. Studies have demonstrated that YTHDF2 can bind to RNase P/MRP endonucleases, leading to the rapid degradation of YTHDF2-bound RNA by directly recognizing m⁶A modifications in TP53 mRNA [49]. Notably, two adjacent m⁶A modification sites have been identified within the coding sequence (CDS) of TP53, separated by only two nucleotides [46]. These sites may be recognized by YTHDF2 either simultaneously or competitively, although the specific impact of single-point mutations at each site remains unclear and warrants further investigation [46]. In addition to YTHDF2, YTHDF3 has also been suggested to interact with TP53 mRNA, indicating a potential broader role of YTH domain family proteins in regulating p53 expression [46].

Additionally, the stability of p53 protein is also modulated by m⁶A methylation (Fig. 3), though this regulation occurs indirectly at the RNA or DNA level [46]. Indeed, the stability of p53 is linked to its phosphorylation at Ser15 and Ser20, sites targeted by kinases such as ATR, ATM, and DNA-PK [50]. Phosphorylation at these residues reduces the binding affinity of p53 to MDM2, an E3 ubiquitin ligase responsible for p53 degradation [51]. Among the kinases, ATM can itself be modified by m⁶A, and its expression is inversely correlated with METTL3 levels [52]. Actually, the m6A-mediated stabilization of p53 protein is likely facilitated by ATM [53]. Additionally, p53 regulates m⁶A RNA methylation, impacting mRNA stability and translation [54]. Research indicates that p53 expression reduces global m6A levels in total RNA from BxPC-3 cells by transcriptionally regulating ALKBH5, a demethylase [54]. This upregulation of ALKBH5 may represent a feedback mechanism for m⁶A modification regulation in pancreatic cancer [54].

Autophagy

The basic mechanism of autophagy

Autophagy, a critical cellular process responsible for the routine recycling and turnover of cellular components, plays an essential role in maintaining cellular homeostasis [55]. Typically activated in response to stress and developmental cues, autophagy is tightly linked to the degradation and repurposing of intracellular constituents [56]. In higher eukaryotes, this process allows the recovery of long-lived proteins and organelles, while short-lived proteins are primarily degraded via the 7ubiquitin-proteasome system [56]. Initially, identified through morphological studies in mammalian cells, molecular investigations into autophagy have largely relied on yeast genetics [57]. Actually, mammalian cells exhibit three primary forms of autophagy, i.e., chaperone-mediated autophagy, macro-autophagy and micro-autophagy [58]. While macro- and micro-autophagy are evolutionarily conserved from yeast to mammals, chaperone-mediated autophagy is predominantly observed in mammalian systems [59]. With respect to the micro-autophagy, it involves the direct engulfment of cytoplasmic material through lysosomal membrane invagination, protrusion, or other deformations [60].

Conversely, macro-autophagy involves the sequestration of cytoplasmic proteins and organelles into double-membrane vesicles, which subsequently fuse with lysosomes, enabling extensive degradation via lysosomal enzymes [61]. In chaperone-mediated autophagy, a cytoplasmic substrate protein binds to a chaperone protein, which directs it to specific lysosomal membrane receptors for translocation into the lysosome [62]. This internalization is completed with the assistance of another chaperone protein located within the lysosomal lumen [62]. In essence, macro-autophagy facilitates the breakdown of macromolecules and damaged organelles, generating energy and alleviating cellular stress and nutrient deficiency [62]. These distinct autophagic pathways are critical for maintaining intracellular homeostasis and enabling adaptation to environmental changes [63]. The mechanism of p53 regulation of Autophagy is shown in Fig. 4.

Fig. 4.

Under cellular stress, p53 can activate proteins such as FAS, BAX, DR5, NOXA, and PUMA to promote autophagy. Additionally, p53 inhibits autophagy by suppressing AMPK and promoting TIGAR.

Regulation of autophagy by p53 in nucleus

In nucleus, p53 promotes autophagy through the regulation of several target genes, including damage-regulated autophagy modulator (DRAM), Isg20L1, Ulk1, and Atg7, often by inhibiting the mTOR pathway, a key negative regulator of autophagy [64], [65], [66], [67]. Further, autophagy is facilitated by AMP-activated protein kinase (AMPK), an evolutionarily conserved sensor of cellular energy status [68]. AMPK phosphorylates the tuberous sclerosis complex (TSC) proteins, TSC1 and TSC2, leading to the downregulation of mTOR activity [69]. Notably, p53 transactivates TSC2 and the β1 and β2 subunits of AMPK [68]. Moreover, genotoxic stress increases the expression of AMPK activators sestrins 1 and 2 in a p53-dependent manner, with sestrin 2 playing a critical role in autophagy induction in p53-proficient cells under various stimuli [70].

Moreover, AMPK can directly phosphorylate p53 in metabolically stressful situations, inducing a protective cell cycle arrest [71]. Overall, the regulation of p53 on autophagy involves a multifaceted interaction of numerous target genes and signaling pathways, underscoring the significance of this regulatory mechanism in maintaining cellular homeostasis and responding to diverse stresses. Additionally, several proapoptotic Bcl-2 protein family members, including Puma, Bax, Bad, and Bnip3, have been identified to exert a proautophagic role [72]. Upon cellular stress, p53 can transactivate these proteins, promoting autophagy by stabilizing p53[72].

Regulation of autophagy by p53 in cytoplasm

Additionally, in the cytoplasm, p53 finely regulates the process of autophagy through multiple mechanisms, playing a crucial role in maintaining cellular homeostasis and responding to various stress challenges. It is known that autophagy is the process of cytoplasmic sequestration and subsequent digestion, allowing cells to adapt to stressful conditions and eliminate damaged, potentially harmful cytoplasmic organelles [55]. Enhanced autophagy is often associated with cell death, representing a failed attempt by the cell to adapt and survive under stress, rather than a lethal catabolic process [73]. p53 can transcriptionally activate genes that induce autophagy (such as DRAM and sestrins 1 and 2), but normal levels of p53 moderately inhibit autophagy [64]. The inhibition of autophagy is mediated by cytoplasmic p53 (as opposed to nuclear p53), and physiological autophagy inducers (such as nutrient deprivation) must deplete the cytoplasmic pool of p53 to induce autophagy [74]. Cytoplasmic p53 (as opposed to nuclear p53) can inhibit AMP-dependent kinase, a positive regulator of autophagy, while activating the mammalian target of rapamycin (mTOR), a negative regulator of autophagy [74]. Additionally, p53 inhibits autophagy through its redistribution from the nucleus to the cytoplasm. Therefore, the removal of the nuclear localization sequence of p53 maximizes its inhibitory effect on autophagy, while the removal of its nuclear output signal completely relieves the inhibitory effect on autophagy [74]. These findings collectively suggest that p53 regulates autophagy by isolating its pro-apoptotic function in the cytoplasm. Specifically, the cytoplasmic pool of p53 inhibits autophagy, whereas nuclear p53 lacks this function. Fig. 4 summarizes the mechanism of autophagy regulated by p53, in which p53 can inhibit autophagy by suppressing AMPK and promoting TIGAR.

Ferroptosis

Iron death: a novel form of cell death

Ferroptosis, a novel form of cell death, is characterized by the accumulation of iron and lipid peroxidation, directly associated with iron metabolism. Iron-responsive factors can influence glutathione peroxidase through diverse mechanisms, leading to a decline in cellular antioxidant capacity and the accumulation of lipid reactive oxygen species, ultimately resulting in the demise of oxidized cells. This mode of cell death is implicated in the pathophysiology of various diseases, including tumors, neurological disorders, kidney injury, hematologic disorders, and others [75]. Ferroptosis exhibits distinctive morphological and functional differences compared to conventional forms of cell death, notably characterized by reduced mitochondrial volume, increased double-layer membrane density, and diminished or absent mitochondrial cristae. Additionally, the biochemical features of ferroptosis include glutathione depletion, impaired activity of glutathione peroxidase 4 (GPX4), failure to metabolize lipid peroxides, and ferrous iron (Fe²⁺) catalyzing lipid peroxidation via a Fenton-like reaction, resulting in substantial reactive oxygen species production [76]. Numerous genes implicated in lipid peroxidation metabolism and iron homeostasis govern this biological process; however, further investigation is warranted to elucidate the precise regulatory mechanisms. Given recent findings demonstrating its involvement in disease pathogenesis, ferroptosis has garnered significant attention in therapeutic interventions and prognostic enhancement.

p53 regulation of SLC7A11 and iron death

Studies have unveiled that p53 repression selectively targets the SLC7A11 gene, encoding a crucial protein integral to the cystine-glutamate antiporter, or XCT, system. This system regulates cysteine uptake from extracellular sources and glutamate efflux from intracellular compartments. Disruption of cysteine uptake diminishes downstream glutathione (GSH) biosynthesis [77]. GSH serves as a vital antioxidant, and its reduced synthesis attenuates GPx4 function, rendering cells more susceptible to ferroptosis (iron-dependent cell death). Notably, p533KR, lacking the DNA damage response, effectively inhibits SLC7A11, inducing ferroptotic cell death. Overexpression of SLC7A11 was found to reverse the tumor growth inhibition elicited by p533KR in a mouse xenograft tumor model, underscoring the role of SLC7A11 inhibition in p53-mediated tumor suppression [78].

Transcriptional regulation of p53 in iron death

H2BUB1, or monoubiquitinated histone H2B lysine 120, represents an epigenetic marker often indicative of active transcription of associated genes. Erastin treatment was observed to reduce h2bub1 labeling on the SLC7A11 gene, leading to a substantial decline in SLC7A11 protein levels. In this mechanism, the p53 protein assumes a pivotal role. Regarded as the “guardian” of cells, p53 orchestrates specific cellular responses to DNA damage, stress, and other stimuli. Within this framework, the promoter region of the SLC7A11 gene becomes the target for p53-mediated recruitment of ubiquitin-specific peptidase 7 (USP7, also known as HAUSP), a deubiquitinase responsible for removing ubiquitin modifications from proteins, thereby maintaining their stability and functionality. USP7-mediated deubiquitination of h2bub1 at the promoter region of the SLC7A11 gene could potentiate suppression of its transcriptional activity, impacting protein expression levels [79].

Association of p53 with iron death biomarkers

Beyond suppressing SLC7A11 and inhibiting GSH biosynthesis, p53 orchestrates iron death by modulating alternative metabolic pathways. Notably, the enzyme spermidine/spermine N1-acetyltransferase 1 (SAT1), a rate-limiting enzyme in polyamine metabolism, emerges as a key player. Intriguingly, p53 activation of SAT1 exerts a tumor growth-suppressive effect. While SAT1 overexpression does not directly affect cell cycle progression or apoptosis, it induces lipid peroxidation and ferroptotic cell death. This phenomenon is associated with upregulation of ALOX15 subsequent to SAT1 induction. Thus, the p53/SAT1/ALOX15 signaling axis contributes to p53-mediated iron death, exerting a positive influence on tumor suppression [80], [81]. Additionally, p53 promotes iron death by enhancing glutaminolysis, activating glutaminase 2, a mitochondrial enzyme pivotal in catalyzing the initial step of glutamine catabolism [82].

In hepatic stellate cells (HSCs), p53 undergoes specific cellular localization modifications, translocating to mitochondria. Within mitochondria, p53 enhances the activity of SLC25A28, a protein implicated in inducing ferroptosis and facilitating abnormal accumulation of redox-active iron. Another p53 target, ferredoxin reductase, regulates iron death induced by erastin and RSL3[83], [84]. Furthermore, p53 impedes the transsulfuration pathway and serine synthesis pathway by inhibiting cystathionine β-synthase (CBS) and phosphoglycerate dehydrogenase (PGD), respectively. This attenuates glutathione synthesis, ultimately promoting iron death. Central to cell biology, mouse double minute 2 homolog (MDM2) plays a pivotal role, serving as the principal E3 ubiquitin ligase responsible for promoting p53 ubiquitination and subsequent degradation. Given p53′s ability to transcriptionally activate MDM2 expression, MDM2 emerges as a downstream target gene of p53 [85].

Recent research unveils a unique role for MDM2 in regulating ferroptosis, independent of its canonical role in p53 regulation. MDM2 and its homolog, MDMX, enhance ferroptosis occurrence by modulating lipid remodeling mediated by peroxisome proliferator-activated receptor alpha and inhibiting ferroptosis inhibitory protein 1 (FSP1). Although MDM2′s effect on ferroptosis is not directly mediated by p53, its induction by p53 suggests a potential regulatory role for p53 in iron death through MDM2 induction. Moreover, p53 regulates the expression of the ferroptosis marker, prostaglandin-endoperoxide synthase 2 (PTGS2 or COX2) [86].

Furthermore, p53 inhibits SLC7A11, indirectly enhancing ALOX12 activity. Specifically, SLC7A11 sequesters ALOX12 by binding to it, preventing ALOX12 from accessing its substrates, polyunsaturated fatty acids (PUFAs), esterified in the cell membrane. Upon downregulation of SLC7A11 by p53, ALOX12 is released, initiating the oxidation of PUFAs in the cell membrane, culminating in ferroptosis. Unlike the p53/SLC7A11/GPX4pathway,the p53/SLC7A11/ALOX12 axis operates independently of GSH biosynthesis and GPx4 activity [87]. Additionally, phospholipase A2 group VI (PLA2G6, iPLA2 β), a calcium-independent phospholipase that cleaves acyl tails from lipid glycerol backbones, releasing oxidized fatty acids, is activated by p53 [88]. Cytoplasmic antioxidants further detoxify oxidized fatty acids. Studies reveal that, independent of GPX4 and FSP1, iPLA2-mediated detoxification of peroxisomal membrane lipids sufficiently inhibits p53/ALOX12-driven iron death.

Moreover, p21, also known as CDKN1A, mediates p53 function in HT-1080 fibrosarcoma cells, delaying cystine deprivation-induced iron death [89]. p53-induced p21 upregulation enhances GSH synthesis, thereby reducing the accumulation of harmful lipid ROS and inhibiting iron death. Notably, p53 prevents colon cancer cells HCT116 and SW48 from undergoing ferroptosis by interacting with DPP4 protein, also known as T cell activation antigen CD26. The multifunctional protease DPP4 is implicated in cell death. When p53 binds to DPP4, it sequesters DPP4 in an enzymatically inactive pool in the nucleus, disrupting its interaction with NADPH oxidase 1 (Nox1) on the cell membrane, thereby attenuating lipid peroxidation and ferroptosis. Conversely, in the absence of p53, DPP4 localizes to the cell membrane, forming a complex with Nox1, leading to heightened lipid peroxidation and increased ferroptosis. Noteworthy, overexpression of Parkin suppresses cysteine deficiency-induced ferroptosis and promotes mitophagy in human fibrosarcoma HT-1080 cells. Mechanistically, cysteine deficiency induces hyperpolarization of the mitochondrial membrane potential, resulting in lipid peroxide accumulation. Given that Parkin is a direct target gene of p53, p53 transcriptionally induces Parkin expression [90]. The mechanism of p53 regulation of Ferroptosis is shown in Fig. 5.

Fig. 5.

p53 disrupts glutathione biosynthesis by inhibiting SLC7A11 gene expression, thereby inducing ferroptosis. It also mediates ferroptosis through the p53/SAT1/ALOX15 signaling axis. p53 simultaneously inhibits cystathionine β-synthase (CBS) and phosphoglyceric acid dehydrogenase (PGD) to block the transsulfuration pathway and serine synthesis pathway, further weakening glutathione synthesis and promoting ferroptosis. However, p53-induced upregulation of p21 enhances GSH synthesis, which helps reduce the accumulation of harmful lipid ROS and inhibits ferroptosis.

Cuproptosis

Cuproptosis: a unique form of cellular demise induced by copper

A recently identified cellular demise mechanism induced by an excess of Cu2 + has been termed cuproptosis. Divergent from established cellular demise pathways such as apoptosis, ferroptosis, and necroptosis, cuproptosis represents a unique form of cell death. In cuproptosis, intracellular copper (Cu) selectively binds to the fatty acid constituents of the tricarboxylic acid (TCA) cycle, forming complexes with fatty acid-modified mitochondrial proteins, ultimately leading to protein aggregation. Crucially, this interaction precipitates the reduction of Fe-S (iron-sulfur) clusters, resulting in protein toxicity and culminating in cellular demise [91].

p53 regulation of cancer metabolism and copper-induced cell death

In the context of energy production and intermediary metabolite generation, cancer cells exhibit distinctive metabolic traits. Unlike normal cells, cancer cells heavily rely on glycolysis for energy production, a phenomenon known as the Warburg effect. Glycolysis provides an effective mechanism for cancer cells to counteract copper toxicity owing to the high concentration of copper ions [92].

A pivotal player in this intricate metabolic orchestration is the tumor suppressor protein p53. Widely recognized as a key metabolic regulator, p53′s functional spectrum extends beyond gene regulation. Intriguingly, p53 exerts direct influence on cancer cells' predominant metabolic pathways, effectively inhibiting glycolysis and promoting a metabolic shift to oxidative phosphorylation. Furthermore, p53 intricately modulates various metabolic processes, including the synthesis of iron-sulfur clusters and copper-chelate glutathione. These attributes suggest that p53 might play an essential role in cellular copper ion handling [93].

By impeding glycolysis and compelling cells to transition to mitochondrial metabolism, p53 may render cells more susceptible to cuproptosis. p53 possesses the capacity to inhibit glucose metabolism by downregulating the expression or functionality of glucose transporters such as GLUT1, GLUT3, GLUT4, and GLUT12, thereby reducing cellular glucose uptake, crucial for glycolysis [94], [95]. Additionally, p53 interferes with several key glycolysis steps. For instance, p53 promotes the breakdown of hK2 mRNA, hindering glucose conversion to glucose-6-phosphate [96]. Through modulation of target genes PFKFB3/4 and TIGAR, p53 further suppresses PFK1 activity, impeding the conversion of fructose 6-phosphate to fructose 1,6-diphosphate [71]. By downregulating pgam1 protein levels, p53 inhibits the conversion of 3-phosphoglycerate to 2-phosphoglycerate, a later stage of glycolysis. Moreover, p53 inhibits eno3 expression, thereby reducing the conversion of 2-phosphoglycerate to phosphoenolpyruvate.

Phosphoenolpyruvate serves as a key intermediate in cellular glycolysis, ultimately contributing to pyruvate formation, which can be metabolized into lactate or fuel the TCA cycle. Importantly, p53 is indispensable for controlling various cellular metabolic functions, including inhibiting LDHA expression. The mechanism underlying this inhibitory effect could involve direct p53 binding to the LDHA promoter or HIF-1 alpha breakdown stimulation. Notably, HIF-1α serves as a critical transcription factor for LDHA. Consequently, intracellular pyruvate accumulation may result from p53′s regulatory activity, providing additional energy for the TCA cycle and oxidative phosphorylation. When glucose restriction reduces intracellular ATP levels, the AMP to ATP ratio increases, activating the AMPK pathway, leading to p53 phosphorylation and activation. This establishes a feedback loop that promotes the transition from glycolysis to oxidative phosphorylation by linking p53 to glucose metabolism [97].

Through various mechanisms, p53 facilitates the TCA cycle and oxidative phosphorylation. p53 stimulates the PDH complex, a pivotal component of the TCA cycle essential for cuproptosis, by promoting dephosphorylation and thereby facilitating pyruvate conversion to acetyl CoA [98]. Additionally, by promoting fatty acid oxidation and inhibiting fatty acid synthesis, p53 enhances acetyl CoA synthesis, initiating the TCA cycle. Glutamate plays a crucial role in the TCA cycle as it can be converted into α-ketoglutarate, a TCA cycle intermediate. p53 facilitates the transcriptional activation of GLS2, promoting glutamate to glutamine conversion. To sustain aspartate metabolism and support the TCA cycle in response to glutamine scarcity, p53 triggers SLC1A3 production [98].

Fe-S clusters are ubiquitous proteins crucial for diverse biological processes, including metabolic stress detection, electron transport, and enzyme catalysis [99]. Research has demonstrated that exposure to high copper concentrations leads to cell demise, accompanied by decreased Fe-S cluster protein stability. Whether the breakdown of Fe-S clusters directly induces copper-induced cell death or represents a collateral effect remains uncertain. Moreover, p53 regulates the expression of numerous genes involved in Fe-S cluster production, suggesting that p53 may influence Fe-S cluster synthesis or stability via a distinct mechanism, thereby impacting cuproptosis [100].

p53 regulation of glutathione generation in cuproptosis

Glutathione (GSH) serves multifunctional roles in cells, acting as a major antioxidant and copper chelator. GSH deficiency can elevate free copper levels, increasing cellular toxicity. Indeed, studies have confirmed that reducing GSH levels using buthionine sulfoximine can enhance copper-induced cell death. Additionally, several investigations have highlighted p53′s essential role in GSH biosynthesis [101]. p53 inhibits SLC7A11 transcription, crucial for cystine import, a GSH precursor, resulting in decreased GSH levels, increased lipid ROS, and ferroptosis. Furthermore, p53 inhibits NADPH synthesis, a potent reductant supplying electrons for GSH renewal, by inhibiting enzymes such as malic enzymes or G6PD, further inhibiting the pentose phosphate pathway [102].

p53 also enhances GSH biosynthesis, bolstering cellular resilience against oxidative stress by activating several metabolism-associated genes such as sesn1/2, TIGAR, and GLS2. Additionally, p53 targets the CDKN1A gene, triggering the Nrf2 antioxidant pathway, leading to increased GSH and NADPH synthesis, further fortifying cellular defenses [103]. In summary, by differentially regulating GSH biosynthesis, p53 may either potentiate or mitigate copper toxicity under physiological or copper-overload conditions. The mechanism of p53 regulation of Cuproptosis is shown in Fig. 6.

Fig. 6.

p53 inhibits glucose metabolism by downregulating the expression or function of glucose transporters (such as GLUT1, GLUT3, GLUT4, and GLUT12), promoting the transition of cells towards mitochondrial metabolism, thereby increasing the sensitivity of cells to cuproptosis. At the same time, it promotes the tricarboxylic acid cycle (TCA cycle) and oxidative phosphorylation through various mechanisms, and may also affect the synthesis or stability of iron-sulfur clusters through unique mechanisms, further affecting the response of cells to cuproptosis.

Mitochondrial p53 regulation of cellular metabolism

Research underscores the significant role of mitochondrial p53 (mtp53) in cellular metabolism and its ability to shield cancer cells against cuproptosis. Mtp53 enhances glycolysis while inhibiting various mitochondrial metabolic mechanisms. Specifically, the GLUT1 cascade facilitates mtp53-mediated glucose absorption. Additionally, mtp53 transcriptionally upregulates PLA2G16 and HK2, augmenting glycolysis rates. Moreover, mtp53 interacts with the mTOR signaling pathway to promote PKM2 activation, further enhancing glycolysis. Conversely, p53 mutants dampen oxidative phosphorylation, partly through interaction with PGC-1α or downregulation of PCK2 expression via the miR-200c-ZEB1/BMI1 Axis. Interestingly, distinct mtp53 variants may exert different effects on mitochondrial metabolism and glycolysis regulation [92].

Pyroptosis

Pyroptosis: an inflammatory form of cell death

Pyroptosis, a programmed form of cell death, predominantly hinges on the formation of plasma membrane pores mediated by gasdermin proteins [104]. This mode of inflammatory cell demise is characterized by cellular swelling, rupture of the plasma membrane, and subsequent release of cellular contents, instigating a robust inflammatory response. Pyroptosis is orchestrated through two principal pathways: canonical and non-canonical inflammasome activation [105]. In the canonical pathway, Gram-negative bacterial invasion prompts the assembly of a multiprotein complex comprising the inflammasome, pattern recognition receptor (PRR), and apoptosis-associated speck-like protein (ASC), culminating in caspase-1 activation. Activated caspase-1 cleaves gasdermin D (GSDMD), liberating its N-terminal fragment, which induces plasma membrane pore formation, leading to interleukin-1β (IL-1β) and IL-18 release, triggering cytolysis and inflammatory cell death [106].

Conversely, the non-canonical pathway involves intracellular lipopolysaccharide (LPS) stimulation, leading to caspase-11/4/5-mediated GSDMD cleavage and subsequent inflammatory cell demise [107]. GSDMD serves as a pivotal effector in both pathways, orchestrating cellular inflammation and demise. Pyroptosis plays a pivotal role in immune regulation and inflammation, aiding in microbial clearance and inflammatory response initiation, thereby preserving tissue homeostasis and immune equilibrium.

p53 regulation of pyroptosis

Research indicates that classical pyroptosis regulation in non-small cell lung cancer (NSCLC) is substantially influenced by the tumor suppressor protein p53. Examination of NSCLC patient tumor samples revealed a positive correlation between p53 expression and pyroptosis occurrence at both mRNA and protein levels [108]. Experimental modulation of p53 expression in A549 cells demonstrated either promotion or suppression of pyroptosis, with additional immunoprecipitation assays confirming the p53-NLRP3 interaction. Furthermore, notable upregulation of p53 expression was observed during pyroptosis in LPS-exposed A549 cells [109]. Collectively, these findings suggest that p53 may promote pyroptosis by interacting with and activating NLRP3.

In irradiated MODE-K cells, increased TP53 gene expression was observed. Employing PTF-α, a p53 transcription inhibitor, revealed the relationship between p53 and GSDMD [109]. Radiation-induced upregulation of p53 and GSDMD expression was reversed by PTF-α, indicating p53′s regulatory control over GSDMD post-radiation. This transcriptional influence of p53 on GSDMD was further corroborated by dual luciferase reporter gene assays, which demonstrated increased GSDMD promoter activity with elevated p53 expression [110]. Additionally, chip-qPCR assays confirmed p53′s association with the GSDMD promoter, elucidating the link between DNA damage, p53 transcriptional activation, GSDMD expression, and pyroptosis induction [111].

Caspase-1 emerges as a pivotal mediator in pyroptosis, orchestrating an inflammatory form of apoptosis by inflammasome activation and intracellular inflammatory response stimulation. Activated caspase-1 facilitates rapid cell rupture and cytokine release, including IL-1β and IL-18, eliciting immune cell responses and culminating in pyroptosis [112]. Gasdermin family proteins play a central regulatory role in pyroptosis, forming pores in cells upon interaction with caspase-1 and other proteins, thereby inducing cell membrane rupture and pyroptosis induction. Notably, p53 has been reported to transactivate caspase-1 and gasdermin family members, thus exerting regulatory control over pyroptosis [113]. The mechanism of p53 regulation of Pyroptosis is shown in Fig. 7.

Fig. 7.

p53 regulates pyroptosis by activating caspase-1 and gasdermin family members, while simultaneously influencing GSDMD.

Endoplasmic reticulum stress

Endoplasmic reticulum stress and cellular stress

Endoplasmic reticulum stress (ER stress) represents a cellular state of stress triggered by dysfunctions within the endoplasmic reticulum (ER)[114]. The ER, a vital subcellular organelle, assumes responsibility for protein folding, modification, and transport. Instances where the endoplasmic reticulum fails to effectively manage protein folding or encounters environmental pressures, viral infections, etc., lead to the accumulation and aggregation of proteins within the ER, consequently inducing ER stress [115]. In response to ER stress, cells initiate a series of signaling pathways such as IRE1, PERK, and ATF6, aiming to rectify ER abnormalities by inhibiting protein synthesis, enhancing protein folding mechanisms, and eliminating aberrant proteins. However, prolonged or severe ER stress can result in adverse outcomes including inflammation, apoptosis, and dysregulated cell cycle, closely associated with various diseases such as diabetes, cancer, and neurodegenerative disorders [116].

ER stress and p53 regulation

Studies have elucidated that ER stress induces the expression of p53. The p53 promoter is specifically recognized by NF-κB, which subsequently activates the promoter. Concurrently, ER stress triggers the activation of NF-κB, thereby inducing p53 expression [117]. Furthermore, ER stress-induced p53 expression is mediated through the activation of the PERK-eIF2α-ATF4 signaling pathway, leading to the upregulation of p53 and its downstream target genes. Additionally, ER stress can elicit the production of reactive oxygen species (ROS), which further activates p53 [118].

Despite inducing p53 expression, ER stress also inhibits p53 function. ER stress, as a significant cellular stress response mechanism, impacts cellular physiology through diverse mechanisms. Particularly, ER stress inhibits p53′s ability to induce apoptosis in response to DNA damage, a state that can be induced by glucose starvation or specific protein folding inhibitors such as thapsigargin and tunicamycin, thus compromising cell survival [119]. The underlying mechanism of this inhibition involves several critical steps. Firstly, ER stress impedes p53 apoptotic activity by localizing wild-type p53 to the cytoplasm where it undergoes degradation. This localization and degradation process engage complex signaling pathways, with GSK3β emerging as a key regulator. GSK3β-mediated phosphorylation of p53 at Ser376 under ER stress conditions prevents its cytoplasmic translocation and consequent apoptotic activity. Moreover, ER stress-induced activation of GSK3β enhances the phosphorylation of p53 at Ser376, prompting its extranuclear translocation and degradation, ultimately inhibiting its function [120], [121]. Additionally, ER stress inhibits the transcriptional activity of p53-dependent genes such as the CDK inhibitor p21 and promotes the degradation of p53 by upregulating the expression and activity of HDM2[122]. Furthermore, ER stress-induced p53 activation stimulates the expression of apoptosis-regulating protein (PUMA) via c/EBP homologous protein (CHOP), while also promoting the expression and nuclear distribution of MDM2, leading to the ubiquitination and downregulation of tumor suppressor p53 [121].

p53, as a pivotal cellular regulator, plays a critical role in maintaining cellular homeostasis and coping with stress. Recent studies have uncovered a novel mechanism through which p53 regulates ER function. Specifically, research has revealed that p53 modulates IRE1 through the α/XBP1 pathway to influence ER function. IRE1α, serving as an ER stress sensor, activates the unfolded protein response (UPR), aiding cells in restoring ER function to maintain cellular homeostasis [123]. Intriguingly, wild-type p53 has been found to inhibit IRE1α, suggesting a negative regulatory role of p53 in ER stress response. Conversely, in the absence of active p53, enhanced activity of the IRE1α/XBP1 pathway promotes ER function [124]. The mechanism of p53 regulation of ER Stress is shown in Fig. 8.

Fig. 8.

Endoplasmic reticulum (ER) stress induces the expression of p53. The p53 promoter is specifically recognized by NF-κB, which subsequently activates the promoter. Concurrently, ER stress triggers the activation of NF-κB, thereby inducing p53 expression.

Disulfidptosis

Disulfidptosis represents a recently identified form of regulatory cell death. Renal cell carcinoma cells prominently display elevated expression of solute carrier family 7 member 11 (SLC7A11), a phenomenon associated with metabolic adaptations [125]. Researchers have elucidated that heightened SLC7A11 expression expedites cytoplasmic nicotinamide adenine dinucleotide phosphate (NADPH) depletion, particularly under conditions of glucose deprivation. Consequently, disulfidptosis ensues, driven by the accumulation of irreducible disulfide bonds, which induces cellular disulfide bond stress, culminating in cellular demise [126].

SLC7A11 facilitates cysteine absorption, a process notably augmented in renal cell carcinoma cells. However, this accumulation of disulfides, including cysteine, provokes cytotoxic cellular stress. To counteract the ramifications of disulfide stress and maintain cellular homeostasis, NADPH functions as a crucial reductant. Nonetheless, the pentose phosphate pathway (PPP) exhibits limited capacity to synthesize NADPH from glucose during glucose scarcity [126]. The increased cysteine uptake facilitated by SLC7A11 exacerbates NADPH depletion, precipitating disulfide molecule accumulation. Consequently, disulfide bonds form within proteins, particularly in the actin cytoskeleton, notably the F-actin protein, leading to the breakdown of the actin filament network and eventual disulfidptosis [127].

Commonly referred to as an oncoprotein, p53 is a pivotal protein primarily involved in cell development, differentiation, and repair, exerting a crucial regulatory role in cells. Moreover, it plays a critical role in suppressing tumors resulting from DNA damage or cellular abnormalities. Activation of p53 occurs in response to DNA damage, stress, or other abnormal conditions. Once activated, p53 upregulates the expression of several genes involved in controlling essential cellular functions such as cell division, DNA repair, and apoptosis [128]. However, information regarding p53′s role in controlling disulfidptosis remains scarce.

Nevertheless, the occurrence of disulfidptosis is intimately linked to SLC7A11, which can be considered the key control point of this cellular process. Notably, research has demonstrated that p53 may occasionally exert a negative regulatory effect on SLC7A11 expression, suggesting a potential avenue for p53-mediated regulation of disulfidptosis [129]. The mechanism of p53 regulation of Disulfidptosis is shown in Fig. 9.

Fig. 9.

p53 may exert a negative regulatory effect on the expression of SLC7A11 and GLUT, thereby further modulating disulfide protein folding.

Discussion

The occurrence and development of cancer involves a complex interaction of cellular mechanisms, usually regulated by key factors such as p53. It is well known that p53 plays an important role in cell cycle arrest, apoptosis and senescence. It also plays a wide range of regulatory roles through its interaction with tumor immunity, various cell death pathways and RNA modification, especially m6A methylation. These multifaceted functions underscore the central role of p53 in regulating tumorigenesis and therapeutic response. Presently, we will discuss the interactions between p53 regulation and cancer Immunity, cell Death and m⁶A methylation.

p53 and cancer immunity

Another crucial function of p53 is its regulation of immune responses, where it influences both innate and adaptive immunity through diverse mechanisms [130], [131]. In both tumor and non-tumor cells, p53 orchestrates an immune network that contributes to tumor suppression. Specifically, in tumor cells, p53 indirectly downregulates PD-L1 expression by upregulating miR-34, enhancing tumor cell sensitivity to anti-tumor immune responses and immunotherapy [132]. Additionally, p53 activates the cGAS-STING pathway, inducing potent anti-tumor activity [133]. In a mouse model of liver cancer, restoring p53 expression induces tumor cell senescence, triggering the release of inflammatory cytokines that initiate an innate immune response to eliminate tumor cells [134]. In hepatic stellate cells, p53-induced senescence exerts tumor-suppressive effects by promoting the polarization of M1 macrophages through the development of a senescence-associated secretory phenotype (SASP), which maintains a tumor-suppressive tumor microenvironment (TME) [135]. In murine myeloid progenitor cells, p53 drives differentiation into mononuclear antigen-presenting cells, thus enhancing anti-tumor immunity [136]. Additionally, loss of p53 in tumor or TME cells significantly alters the immune microenvironment from tumor-suppressive to immunosuppressive, fostering immune tolerance or escape by tumor cells, or creating an inflammatory environment conducive to metastasis [137], [138]. Interestingly, mutant p53 can promote immune evasion in tumor cells [139] and in some cases, mutant p53 may generate neoantigens, offering novel targets for immunotherapy [140]. Furthermore, p53 also participates in autoimmune responses and in defending against various pathogens [141]. Notably, not all p53-related immune activities are beneficial, as p53 can inhibit the proliferation and function of certain T-cell subtypes [142], [143]. For instance, p53 suppresses the proliferation of antigen-nonspecific CD4 + T cells, a process that can be reversed by T-cell receptor (TCR) signaling [143].

p53-mediated cancer cell death

Additionally, p53 plays a pivotal role in determining cancer cell fate by regulating various forms of cell death, including ferroptosis, cuproptosis, autophagy, disulfidoptosis, endoplasmic reticulum stress and pyroptosis [144], [145], [146]. Through transcriptional control, p53 modulates the expression of key proteins such as PUMA, Bax, Bcl-2, SLC7A11, GSDMD, and PEAK [146], [147], thereby influencing the initiation and execution of programmed cell death. This regulatory capacity is essential for maintaining cellular balance within the tumor microenvironment (TME) [148].

p53 and m⁶A methylation

Recently, RNA modifications (particularly m⁶A methylation) have gained attention as regulators of gene expression and stability in cancer biology [149]. m⁶A modification regulates the proliferation, differentiation, and survival of cancer cells by affecting various aspects of RNA metabolism, such as splicing, translation, and degradation [150]. Meanwhile, p53 influences global m⁶A methylation levels by transcriptionally regulating ALKBH5 [54].

Crosstalk between p53 and cancer immunity, cell death, m⁶A methylation

Indeed, the regulation of p53 on the cancer immunity, cell death, and m⁶A methylation indicates a complex crosstalk between these mechanisms. For example, m⁶A modifications can influence the stability of transcripts involved in immune responses, such as cytokine signaling molecules, thereby reshaping the immune landscape within the tumor microenvironment (TME) [151]. In turn, the capacity of immune system to eliminate tumor cells may depend on the specific form of cell death triggered by p53, further modulating immune activity within tumors [131]. Moreover, p53 can regulate m⁶A-modifying enzymes, thereby influencing global m⁶A methylation levels [54].

Gain-of-function of mutant p53

p53, as a tumor suppressor, plays a pivotal role in responding to DNA damage, maintaining genomic stability and inducing apoptosis. However, more than 50 % of tumors harbor mutations in p53 [152]. Unlike wild-type p53, mutant p53 not only loses its tumor-suppressive functions but also acquires novel oncogenic properties, termed “gain-of-function” (GOF) mutations [153]. These GOF activities allow mutant p53 to drive cell proliferation, invasion, apoptosis resistance, and chemoresistance by activating specific signaling pathways [151]. Additionally, mutant p53′s GOF is intricately involved in regulating the TME, metabolic reprogramming, and the epigenetic regulation of gene expression [34]. Thus, understanding the GOF of mutant p53 is essential for elucidating tumor progression mechanisms and for the development of targeted therapeutic strategies.

Mutant p53 and TME

Tumor cells with p53 mutations promote immune evasion by creating an immunosuppressive TME. The interactions between TP53-mutant cancer cells and the TME, particularly with myeloid cells and regulatory T cells (Tregs), play a crucial role in tumor progression and immune evasion. Myeloid cells, including macrophages and neutrophils, exhibit phenotypic and functional alterations in the presence of TP53-mutant cancer cells [154]. These changes often lead to an immunosuppressive microenvironment, promoting tumor growth and metastasis.

In the TME, macrophages can adopt different functional states, commonly categorized as M1 (classically activated) or M2 (alternatively activated) [155]. For example, M2 macrophages are typically associated with immunosuppression and therapeutic resistance in various cancers [156], [157]. Studies have shown that p53 mutations in cancer cells drive the polarization of macrophages towards the M2 phenotype [158], [159]. Actually, this polarization is linked to an immunosuppressive microenvironment that supports tumor growth, invasion, and metastasis [155]. Moreover, mutant p53 cancer cells may also secrete factors such as CSF-1 (colony-stimulating factor 1)[160], IL-10 (interleukin-10)[158], and TGF-β (transforming growth factor-β)[161], which are known to induce M2 macrophage polarization. In addition to disrupting the tumor-suppressive functions of wild-type p53, certain missense mutations endow mutant p53 proteins (mutp53) with GOF activities [151]. These GOF activities significantly alter the behavior of tumor cells by affecting protein interactions and transcriptional programs. Additionally, studies have shown that p53-mutant cancer cells can actively reprogram macrophages into a tumor-supportive anti-inflammatory state [162]. Specifically, GOF mutp53 in colon cancer cells selectively releases exosomes enriched with miR-1246[158]. Upon uptake by neighboring macrophages, miR-1246-dependent reprogramming occurs, favoring cancer progression [158].

Additionally, Treg cells are key components of the immunosuppressive network within the TME, helping cancer cells evade the immune system and promoting tumor progression [163]. They can be recruited into the TME through various chemokines and enhance tumor growth by suppressing antitumor cells, such as cytotoxic CD8 + T cells. Actually, a study showed that p53 deficiency in prostate, ovarian and pancreatic cancers increased the number of Tregs in the TME [164]. This was linked to the suppression of miR-34a, leading to increased CCL22 production and enhanced Treg recruitment to the TME [164]. Besides, Tregs from patients with TP53-mutant acute myeloid leukemia (AML) exhibit distinct metabolic characteristics. Compared to controls, these Tregs show enrichment of gene sets related to glycolysis, fatty acid metabolism, and oxidative phosphorylation [165]. This suggests that TP53-mutant cancers may enhance Treg energy production by altering glucose and fatty acid usage in the AML context.

Overall, the complex interactions between TP53-mutant cancer cells, myeloid cells, and Tregs establish a highly immunosuppressive TME that drives tumor growth, invasion, and resistance to immunotherapy. Elucidating these key interactions is critical for developing novel therapeutic strategies targeting TP53-mutant tumors and overcoming their mechanisms of immune evasion.

Mutant p53 and ferroptosis

Compared to wild-type p53 (wtp53), mutant p53 (mutp53) plays a distinct role in regulating ferroptosis [166]. These mutations often result in the loss of p53 function or the acquisition of novel functions that alter cellular sensitivity and resistance to ferroptosis.

For example, in esophageal and lung cancers, mutant p53 suppresses the expression of SLC7A11 by interacting with the master antioxidant transcription factor NRF2, promoting ROS accumulation and inducing ferroptosis [167]. Additonally, mice harboring p53^3KR mutations, in which lysine residues 117, 161, and 162 are substituted with arginine, exhibit defective deacetylation, fail to regulate the cell cycle and apoptosis like wild-type p53, but suppress SLC7A11 expression and induce ferroptosis [75]. Moreover, in tumors with mutant p53, exogenous expression of SLC7A11 promotes resistance to ferroptosis-inducing drugs, further indicating that mutant p53 sensitizes cancer cells to ferroptosis by inhibiting SLC7A11[167]. However, Wang et al. generated p53^4KR mutant mice (K98R + 3KR), which were deficient in tumor growth suppression and also failed to inhibit SLC7A11 expression or induce ferroptosis [168]. Indeed, p53^4KR mice developed tumors earlier than p53^3KR mice [168]. Besides, in hepatic stellate cells, the p53 S392A mutant impairs BRD7 binding and mitochondrial translocation of p53, thereby inhibiting ferroptosis [82]. Recent studies have suggested that mutant p53 protects triple-negative breast cancer from ferroptosis in vivo through NRF2-dependent regulation of Mgst3 and Prdx6 (genes encoding glutathione-dependent peroxidases that detoxify lipid peroxides)[169].

Mutant p53 and cuproptosis

Mutant p53 enhances glycolysis and inhibits mitochondrial metabolism through various mechanisms [170]. For instance, mutp53 increases glucose uptake via the RhoA-ROCK-GLUT1 cascade [171] and promotes glycolysis by transcriptionally inducing the expression of HK2[172]and PLA2G16[173]. Mutp53 also enhances glycolysis by promoting mTOR signaling-mediated phosphorylation of PKM2[174]. Additionally, mutant p53 downregulates oxidative phosphorylation by interacting with and inhibiting PGC-1α function [175] or downregulating PCK2 via the miR-200c-ZEB1/BMI1 axis [176]. Importantly, different mutp53 proteins may have distinct roles in regulating glycolysis and mitochondrial metabolism [177]. Mutant p53 also enhances lipid synthesis and inhibits fatty acid oxidation, thereby reducing the availability of acetyl-CoA for the tricarboxylic acid cycle. Mechanistically, mutp53 cooperates with SREBPs to activate the mevalonate pathway [178], transcriptionally activates PLA2G16 to increase phospholipid synthesis [179], and inhibits AMPK signaling to support anabolic processes [180], [181]. Collectively, these studies suggest that mutp53 may protect cancer cells from cuproptosis by regulating metabolism.

Mutant p53 and m⁶A

Mutant p53 contributes to the cancer progression by modulating proteins within the m⁶A transcriptional network. In glioma studies, researchers observed that mutant p53, unlike its wild-type counterpart, physically interacts with the SVIL protein, recruits the H3K4me3 methyltransferase MLL1, and activates the transcription of the m⁶A reader protein YTHDF2, fostering an oncogenic phenotype. The aberrant upregulation of YTHDF2 significantly downregulates the expression of several tumor suppressor transcripts marked by m⁶A, including CDKN2B and SPOCK2, thereby promoting oncogenic reprogramming and tumorigenesis [182].

Mutant p53 and autophagy

Studies have shown that the p53R175H or p53R273H mutants inhibit autophagy by transcriptionally repressing the expression of key downstream p53-responsive autophagy-related genes, such as BECN1, DRAM1, ATG12, TSC2, SESN1/2, and P-AMPK [183]. This repression blocks the formation of autophagic vesicles and their fusion with lysosomes, leading to autophagy arrest [183]. Correspondingly, knocking down these mutants in cancer cells enhances autophagy by affecting signaling at various stages of the autophagy process, while also stimulating the mTOR signaling pathway [184]. However, it is important to note that both p53 loss and missense mutations can significantly impact the mTOR signaling pathway, where the enhanced binding of Rheb to the lysosomal membrane promotes the formation of the active mTORC1 complex [184].

In addition, the autophagy-inhibiting effects of mutant p53 proteins are also attributed to their transcription-independent functions [185]. Certain p53 mutants (e.g., p53R175H, L194F, R273H) lose the wild-type ability to form complexes with endogenous Bcl-2 or Bcl-XL [185]. This loss of wild-type function prevents these interactions, enabling cancer cells harboring mutant p53 to maintain the inhibitory interaction between Beclin-1 and Bcl-2 family proteins [185]. Furthermore, through mTOR activation, these mutants negatively affect the expression and phosphorylation of Beclin-1, thereby inhibiting Beclin-1 s role in autophagy. Similarly, the p53G199V mutant acquires the ability to regulate STAT3 phosphorylation through mTOR activation [186], which promotes the transcriptional activation of HIF-1, speculated to contribute to autophagy inhibition. As part of their gain-of-function, certain cancer-related p53 mutants also indirectly block autophagy through protein–protein interactions by activating several growth factor receptors, such as TGFBR, EGFR, and IGFR [187]. This leads to sustained PI3K/Akt/mTOR signaling, further inhibiting autophagy [187]. Moreover, in breast cancer cells, the p53R273H mutant has been directly correlated with Akt phosphorylation, which in turn affects the activity of its downstream target, mTOR.

Overall, all the findings highlight the critical insight that the autophagy-inhibiting effects of mutant p53 seem to primarily focus on the classical AMPK-mTOR signaling pathway, either through transcriptional dysregulation or gain-of-function-mediated protein–protein interactions. Additionally, the p53 functions in different context is depicted in Table 1.

Table 1.

p53 function happens in a specific context.

Context	p53 function	Genes regulated byp53	References
Autophagy	In the nucleus, p53 promotes autophagy by inhibiting mTOR and activating AMPK, regulating genes such as Dram, Isg20L1, Ulk1, Atg7, and Bcl-2 family members like Puma. In the cytoplasm, it inhibits autophagy through nuclear-to-cytoplasmic redistribution	DRAM; ULK1; ATG7; Sestrins 1; Sestrins 2; AMPK; TSC2	[60], [61], [62], [63], [64], [65], [66]
Ferroptosis	p53 inhibits SLC7A11 to reduce GSH, enhancing ferroptosis, while activating SAT1 for lipid peroxidation. In hyperlipidemia, p53 upregulates SLC7A11 to protect smooth muscle cells	SLC7A11;GSH;GPx4;SAT1;MDM2;PTGS2;p21;DPP4	[69], [71], [72], [79]
Cuproptosis	p53 enhances copper toxicity in cancer cells by inhibiting glycolysis, promoting mitochondrial metabolism, and reducing glucose uptake (GLUT1/GLUT3). It also lowers GSH by repressing SLC7A11. Mitochondrial p53 (mtp53) boosts glycolysis and alters mitochondrial pathways, affecting the response to copper toxicity	SLC7A11;GSH; GPx4; SAT1; MDM2; PTGS2; DPP4; GLUT1; GLUT3	[83], [84], [85], [90], [91], [92], [93], [94], [95]
pyroptosis	p53 promotes pyroptosis by interacting with NLRP3, regulating GSDMD, and activating caspase-1. It also enhances cytokine release (IL-1β, IL-18), driving the immune response and further promoting pyroptosis	NLRP3; GSDMD; Caspase-1;ASC	[99], [100], [101], [102], [103], [92], [104]
disulfidptosis	p53 may indirectly influence disulfidptosis by regulating SLC7A11 expression	SLC7A11	[120]
ER Stress	p53 modulates ER function by negatively regulating IRE1α, while its absence enhances IRE1α/XBP1 activity, promoting ER function	IRE1α	[114], [115]
M6A	p53 can transcriptionally regulate the expression of ALKBH5, thereby affecting global m6A levels.	ALKBH5	[143]
TME	p53 modulates immune responses, regulates angiogenesis, remodels the extracellular matrix, and influences stem cell activity in the tumor microenvironment (TME), impacting tumor initiation and progression.	COX2;IRF5;ULPBP1/2;THBS1;CCL2;VEGF;CXCL1;TSAP6;HMG1;TAP1;PD-L1;	[34], [35], [36], [37], [38], [39], [40], [41], [42]

Conclusion and perspective

p53 is a pivotal tumor suppressor that governs a wide array of cellular processes, profoundly influencing both cancer progression and therapy resistance. Its regulatory functions encompass modulation of the TME, control of m⁶A RNA modifications and regulation of various forms of PCD. Presently, we systematically and comprehensively summarize the multiple roles of p53 in the development of cancers from the regulation of TME, m⁶A Modification and diverse PCD. Additionally, the function roles of p53 including the wild-type and mutant p53 in different context are also summarized. All the findings are listed as following.

• (1)Loss of p53 function promotes chronic inflammation, immune suppression and tumor growth, while its reactivation enhances immune-mediated tumor clearance. Additionally, understanding the GOF of mutant p53 is essential for elucidating tumor progression mechanisms and the complex interactions between p53-mutant cancer cells, myeloid cells and Tregs establish a highly immunosuppressive TME that drives tumor growth, invasion and resistance to immunotherapy.
• (2)M⁶A directly affects the stability of p53 mRNA and interacts with key signaling pathways, including NF-κB, Wnt and PI3K/Akt. Moreover, p53 may regulate m⁶A RNA modification, thereby influencing its own function and the expression of downstream target genes. Additionally, in its mutant form, p53 promotes oncogenic phenotypes by destabilizing tumor suppressor transcripts through its interactions with m⁶A-related proteins. This underscores the complex regulatory feedback loop between p53 and m⁶A, highlighting the potential of targeting m⁶A modifications in p53-driven cancers.
• (3)With a dual role in autophagy regulation, p53 balances cellular stress responses through distinct actions in the nucleus and cytoplasm. In the nucleus, p53 promotes autophagy by regulating genes such as DRAM and AMPK while inhibiting the mTOR pathway. Conversely, cytoplasmic p53 suppresses autophagy by inhibiting AMPK and activating mTOR. Mutant p53 further impairs autophagy by repressing the transcription of autophagy-related genes and interacting with key regulators like Beclin-1. These insights underscore the complex involvement of p53, both wild-type and mutant, in autophagy regulation, contributing to tumor progression and resistance to therapy.
• (4)p53 plays a crucial role in regulating various cell death pathways, including ferroptosis, cuproptosis, disulfidptosis and pyroptosis. It promotes metabolic reprogramming by modulating glycolysis and oxidative phosphorylation, increasing susceptibility to cuproptosis. In pyroptosis, p53 interacts with the NLRP3 inflammasome and regulates GSDMD expression, enhancing pyroptotic signaling. Endoplasmic reticulum stress suppresses p53, weakening its apoptotic function. Additionally, mutant p53 enhances glycolysis, inhibits mitochondrial metabolism, and reduces sensitivity to ferroptosis and cuproptosis.

All these findings suggest that regulation of p53 on the cancer immunity, cell death and m⁶A methylation indicates a complex crosstalk between these mechanisms. However, there are still challenges persist in the cancer research and therapy.

First, the inherent complexity of p53 complicates the development of targeted therapies. Its dual role in autophagy—promoting cell survival under nutrient deprivation while inducing cell death under stress—underscores the need for a nuanced understanding of how to modulate p53 activity. Inappropriate targeting could inadvertently support tumor cell survival.

Secondly, limited research on the involvement of p53 in emerging programmed cell death pathways, such as disulfidptosis and pyroptosis, hinders our understanding of their roles in cancer progression and the identification of novel therapeutic targets.

Additionally, insufficient studies on the regulation of p53 on m⁶A modifications create a knowledge gap regarding its influence on cellular processes and tumorigenesis, slowing the development of innovative treatment strategies.

In final, the heterogeneity of TP53 mutations poses a significant challenge, resulting in diverse tumor phenotypes across patients, which complicates personalized treatment approaches. This variability can lead to inaccurate prognostic assessments and treatment resistance.

Overall, to address these challenges, future research must focus on elucidating the dual roles of p53 to guide more precise therapeutic interventions. Expanding studies on the involvement of p53 in disulfidptosis and pyroptosis could uncover new therapeutic targets. Additionally, prioritizing research on its regulation of m⁶A modifications will also clarify key mechanisms in cancer development. Finally, precision medicine strategies should integrate multi-omics data to develop individualized treatment approaches based on the specific impact of TP53 mutations, while fostering collaboration between basic science and clinical research to accelerate the development of novel therapies.

Ethical statement

The did not include any human subjects.

CRediT authorship contribution statement

Xiangyu Wang: Methodology, Investigation, Data curation, Writing – original draft. Jianhua Yang: Methodology, Validation, Investigation, Data curation. Wanting Yang: Methodology, Validation, Investigation. Haiyang Sheng: Methodology, Investigation, Data curation. Buyun Jia: Methodology, Investigation, Data curation. Peng Cheng: Resources, Supervision. Shanshan Xu: Resources, Supervision. Xinhui Hong: Resources, Supervision. Chuanwei Jiang: Resources, Supervision. Yinfeng Yang: Conceptualization, Resources, Supervision. Ziyin Wu: Conceptualization, Resources, Supervision. Jinghui Wang: Conceptualization, Resources, Supervision, Project administration, Funding acquisition, Writing – original draft, Writing – review & editing.

Funding

Thanks for the Outstanding Youth Research Project of Anhui Department of Education (No. 2022AH020042), Major Scientific Research Project of Anhui Provincial Department of Education (Grant No. 2024AH040146), the Anhui Province quality projects (Grant No. 2023sdxx027)and the Middle-aged Young Teacher Training Action Project of Anhui Provincial Department of Education (Grant No. JNFX2023020).

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Biographies

Xiangyu Wang, born in 2001, is currently pursuing a master's degree in pharmacology at Anhui University of Chinese Medicine, under the supervision of Professor Jinghui Wang. His research focuses primarily on pharmacology and bioinformatics, dedicated to exploring the pharmacological effects and molecular mechanisms of traditional Chinese medicine and its active components. Xiangyu Wang has demonstrated outstanding academic performance, participating in numerous research projects that showcase his solid research capabilities and innovative spirit. He has a strong interest in the intersection of pharmacology and bioinformatics and aims to advance the modernization of traditional Chinese medicine and new drug development through scientific research. Outside of his academic pursuits, Xiangyu Wang is passionate about fitness and emphasizes the importance of comprehensive physical and mental health, believing that a healthy body is the foundation for efficient research.

Jianhua Yang is a current master's student at the School of Medical Information Engineering, Anhui University of Chinese Medicine, specializing in the field of Chinese Medicine Information Science. He demonstrates a strong interest in the integration of traditional theories of Chinese medicine with modern information technology and is dedicated to exploring the application of Chinese medicine information in contemporary medicine. In terms of academic research, Yang Jianhua actively participates in research projects at the school, continuously improving his research skills and professional competence through practical experience.

Wanting Yang graduated from Anhui University of Traditional Chinese Medicine with a master's degree in pharmacology under the guidance of Professor Jinghui Wang. She currently works in research and development at Nanjing Kanion Pharmaceutical, focusing on pharmacology and bioinformatics. Wan-Ting Yang is dedicated to studying the pharmacological effects and molecular mechanisms of traditional Chinese medicine and natural products, promoting the modernization of traditional Chinese medicine and the development of new drugs. She has demonstrated outstanding performance in research, participating in several significant research projects and presenting numerous papers at national and international academic conferences, showcasing her solid research skills and innovative spirit. In addition to her professional expertise, Wan-Ting Yang has a deep passion for reading, traveling, and photography. She looks forward to continuing to explore the forefront of pharmacology in her future career and making greater contributions to the field of human health.

Haiyang Sheng is a highly accomplished biostatistician with a solid educational background and extensive experience in clinical trial design and data analysis. He earned his Ph.D. and M.A. in Biostatistics from the State University of New York at Buffalo. Currently he is a Senior Manager of Biostatistics in Late Oncology at Bristol Myers Squibb, where he collaborates on clinical study design, data analysis, and reporting. His expertise encompasses a range of statistical methodologies, including graphical multiple testing, survival data analysis, and machine learning techniques. Prior to joining Bristol Myers Squibb, he has also worked on cancer epidemiological research at Roswell Park Comprehensive Cancer Institute. Haiyang's research work has been published in reputable journals, and presented at major conferences like the American Society of Clinical Oncology and the American Association for Cancer Research.

Buyun Jia, an assistant researcher, is employed at the College of Integrative Medicine at Anhui University of Chinese Medicine. Dr. Buyun Jia currently serves as a council member of the Clinical Pharmacy Branch of the China Association of Traditional Chinese Medicine. Dr. Buyun Jia has been engaged in the pharmacological research of traditional Chinese medicine and its formula as well as the screening of anti-tumor components in traditional Chinese medicine and the research on nanostructure drug delivery systems of them.

Peng Cheng, male, is an associate chief physician in the Department of Gastroenterology of the First Affiliated Hospital of Anhui University of Chinese Medicine and a postgraduate supervisor. Professional and technical expertise: Clinical and endoscopic diagnosis and treatment of early-stage digestive tract cancer and precancerous diseases.

Shanshan Xu is a professor and master tutor at Department of Public Health and General Medicine in Anhui University of Chinese Medicine. She participated in the design and review of the manuscript. Professor Xu's research interests include TCM prevention and treatment of autoimmune diseases, molecular epidemiology of chronic diseases, TCM informatics, and evidence-based medicine. Professor Xu has published more than 50 international peer-reviewed journals as first author or co-first author.

Hong Xinhui is currently a lecturer in the School of Integrated Traditional Chinese and Western Medicine, Anhui University of Traditional Chinese Medicine. The main research direction is the anti-tumor pharmacology of integrated traditional Chinese and Western medicine.

Jiang Chuanwei is currently an experimenter in the College of Integrated Traditional Chinese and Western Medicine of Anhui University of Traditional Chinese Medicine. The main research direction is the anti-tumor pharmacology of integrated traditional Chinese and Western medicine.

Yinfeng Yang Associate Professor, Master's Supervisor, Member of the China Association of Chinese Medicine Informatics, and Deputy Director of the Department of Intelligent Medicine.In terms of research, she has been engaged in the intersection of artificial intelligence and traditional Chinese medicine in recent years, with a focus on screening active components of traditional Chinese medicine, predicting targets, and exploring molecular mechanisms. She has published over 50 academic papers in domestic and international journals such as Phytomedicine (Q1, top) and J. Agric. Food Chem. (Q1, top), including 16 SCI papers as the first or corresponding author. Her papers have been cited nearly 4,000 times, with an h-index of 15. She has co-authored an academic monograph, applied for and been granted one patent, with another patent under substantive examination. She has led one key natural science research project of Anhui Provincial Higher Education Institutions, one Anhui Provincial Education Department project for the training of young and middle-aged teachers in colleges and universities, and one key natural science research project and one high-level talent introduction project at Anhui University of Chinese Medicine. She has been invited to review for more than 10 well-known international journals, including Pharmacological Research.

Ziyin Wu, a Professor and head of the Genomics Research Platform at the State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, has made pivotal contributions to the design and review of this manuscript. With a distinguished academic record and professional insights, Professor Wu's research spans a wide range of disciplines, including pharmacogenomics, the pharmacology of traditional Chinese medicine, and neuropharmacology. His work is distinguished by the innovative application of multi-omics technologies to drug discovery, with a special focus on identifying and understanding the active components within traditional Chinese medicinal herbs.

Jinghui Wang, Professor and Ph.D. supervisor at Anhui University of Chinese Medicine, is a Principal Investigator (PI) and recipient of the inaugural Anhui Provincial Outstanding Youth Science Fund (awarded by the Department of Education). He focuses on cutting-edge research at the intersection of artificial intelligence and medicine, leveraging machine learning and deep learning algorithms to deeply analyze the pathological and molecular characteristics of 33 cancer types and over 20,000 malignant tumor samples. Through self-developed algorithms, he achieves efficient programming and supercomputing capabilities on CPU-GPU hardware architectures, advancing mathematical modeling and applied research in medicine using deep learning and molecular dynamics simulations. In recent years, he has published over 60 papers as the first or corresponding author in journals. He has been invited to serve as a reviewer for more than 10 prestigious international journals, including Advanced Science. Wang has led projects funded by the National Natural Science Foundation, the Anhui Provincial Youth Project, and high-level talent projects at Anhui University of Chinese Medicine. His international accolades include the “Best Researcher Award” and “Outstanding Scientist Award.”