p53 Regulation of Non-Apoptotic Cell Death: Research Advances and Therapeutic Potential

Since its discovery in 1999, p53 has been a focal point of research as a critical transcription factor regulating multiple cell death pathways. Initially recognized as a key regulator of programmed cell death—apoptosis—p53 eliminates damaged or cancerous cells to maintain cellular homeostasis. As research progressed, scientists realized that p53’s functions extend far beyond apoptosis. Recent studies show that p53 also regulates various non-apoptotic cell death (NACD) pathways, including ferroptosis, necroptosis, pyroptosis, autophagy-dependent cell death, entotic cell death, parthanatos, and paraptosis, as well as less-defined pathways such as PNAPoptosis, NETotic cell death, and disdiffproosis. These novel cell death mechanisms play significant roles in tumor suppression and other pathological conditions.

Fig. 1 Diverse Types of Cell Death

Ferroptosis: Lipid-Driven Cell Demise

Ferroptosis is a form of programmed cell death triggered by iron-dependent lipid peroxidation. Research shows that p53 regulates ferroptosis by modulating key components, notably by downregulating SLC7A11, a cystine/glutamate antiporter. This process activates ALOX12, a critical enzyme that promotes lipid peroxidation, thereby inducing ferroptosis. Further studies reveal that ALOX12 is selectively recruited to membrane-bound phosphatidic acid (PA), a process enhanced by proteins like P3HDA2 and GPAT3. These findings highlight p53’s role in amplifying oxidative stress, offering new insights into its tumor-suppressive functions, particularly in triple-negative breast cancer (TNBC), where eliminating mutant p53 can trigger ferroptosis and lead to tumor regression.

Fig.2 p53-Regulated Ferroptosis

Necroptosis and Pyroptosis: Inflammation and Beyond

As research deepens, p53’s roles in necroptosis and pyroptosis have become increasingly clear. Necroptosis is a programmed form of necrosis closely linked to inflammation, while pyroptosis involves inflammasome activation. Studies indicate that p53 modulates key signaling molecules, such as RIPK1/3 for necroptosis and CASP1/11 for pyroptosis. For example, in hepatocellular carcinoma, chemotherapeutic agents activate p53-mediated checkpoint kinase 1 (CHK1), partially inducing pyroptosis and reducing tumor cell survival. These discoveries expand p53’s potential applications in inflammation-related diseases and cancer therapy.

Fig.3 p53-Regulated Necroptosis and Pyroptosis

p53 in Autophagy-Dependent Cell Death

Autophagy is a conserved catabolic process where cytoplasmic components are sequestered into phagophores, forming autophagosomes that deliver cargo to lysosomes for degradation, typically promoting cell survival under stress conditions like nutrient deprivation. However, dysregulated or excessive autophagy can lead to autophagy-dependent cell death. p53 regulates autophagy through multiple mechanisms, inducing this form of cell death. In HCT116 colon cancer cells, inhibition of sphingosine kinase 1 (SPHK1) activates p53-mediated autophagy-dependent cell death, which can be reversed by knocking down key autophagy regulators Beclin 1 and ATG5. Additionally, p53 promotes autophagy-dependent cell death by transcriptionally activating tumor protein p53-induced nuclear protein 1 (TP53INP1) across various cell types. Anti-tumor agents like ginsenoside Rh4 and resveratrol induce this cell death in colorectal and lung adenocarcinoma cells, respectively, via p53 activation. Autophagy-mediated cell death may overlap with apoptosis or ferroptosis, necessitating careful differentiation of death types.

Fig.4 p53-Regulated Autophagy-Dependent Cell Death

p53 in Entotic Cell Death

Entosis is a process where live cells are engulfed by non-phagocytic cells, forming “cell-in-cell” structures, with cytoskeletal rearrangements driving cell invasion. Typically, engulfed cells undergo entotic cell death. In mitotic epithelial cells with DNA damage, p53 promotes entotic cell death by activating Rho family GTPase 3 (RND3), clearing aneuploid daughter cells to maintain genomic integrity. Interestingly, mutant p53 can also promote entosis-like “cell-in-cell” structures, which may have pro-tumorigenic effects as engulfed cells may evade death. Additionally, p53-driven entotic cell death in cortical progenitor cells is linked to PALS1-associated microcephaly.

Fig.5 p53-Regulated Entotic Cell Death

p53 in Apoptosis-Inducing Factor-Dependent Necrosis

Parthanatos is a non-apoptotic cell death triggered by DNA damage. In mild DNA damage, poly(ADP-ribose) polymerase 1 (PARP1) is activated to repair DNA, promoting cell survival. However, extensive DNA damage leads to PARP1 overstimulation, producing excess poly(ADP-ribose) (PAR) polymers, which trigger the release of apoptosis-inducing factor (AIF) from mitochondria. In the cytoplasm, AIF forms a complex with macrophage migration inhibitory factor (MIF), translocates to the nucleus, and cleaves genomic DNA into large fragments, causing parthanatos. In human colorectal cancer (CRC), breast cancer cells, and mouse embryonic fibroblasts, p53 enhances PARP1 enzymatic activity in response to reactive oxygen species (ROS)-induced DNA damage, activating parthanatos. In CRC, when kinase AKT is inhibited, p53 promotes PAR polymerization by directly interacting with PARP1, suppressing CRC cell growth. Additionally, p53 may transcriptionally activate AIF to further promote parthanatos. However, in the presence of BRAF V600E mutations, TP53 deficiency sensitizes tumor cells to E26 transformation-specific (ETS) inhibitor-induced parthanatos, indicating context-dependent roles of p53 in parthanatos-mediated tumor suppression. Fig. 3c is expected to be a schematic illustrating the molecular mechanisms of parthanatos, highlighting p53’s regulation through enhanced PARP1 activity, PAR polymerization, and AIF transcriptional activation.

Fig.6 p53-Regulated Apoptosis-Inducing Factor-Dependent Necrosis

Therapeutic Potential: Targeting p53-Regulated NACD

The article further explores the therapeutic potential of targeting p53-regulated non-apoptotic cell death (NACD). Researchers have developed various drugs targeting p53-mediated ferroptosis, necroptosis, and pyroptosis for treating cancer, organ damage, immune degenerative diseases, and infections. For example, certain compounds selectively target cancer cells by inducing ferroptosis, while inhibiting mutant p53 in TNBC significantly enhances ferroptosis effects. Moreover, p53-regulated NACD exhibits high context-dependency in response to specific stressors and signals, interacting with other cell-type-specific regulators to determine cellular fate.

Fig.7 Therapeutic Applications of Targeting p53-Regulated NACD

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