The multifunctional selective autophagy receptor and stress-responsive scaffold protein SQSTM1, commonly designated as p62, operates as a central molecular integrator shaping tumor initiation, progression, metastasis, and therapeutic resistance across human malignancies, according to an extensive scientific review published in Frontiers in Cell and Developmental Biology. Investigators Yinghong Liu, Guoqing Xue, Yuechuan Liu, Tianyu Zhou, Bingke Cheng, Jingxuan Wu, Xiaojing Zhang, Zhaolin Sun, Peng Chu, and Jincheng Song from Dalian Medical University synthesized structural, regulatory, and pharmacological research to evaluate how the cellular adapter coordinates proteostasis, oxidative stress responses, inflammation, and metabolic reprogramming. Their analysis underscores that SQSTM1/p62 cannot be defined as a uniform oncogene or a simple tumor suppressor, because its operational output varies significantly depending on cellular lineage, tumorigenesis stage, autophagic competence, subcellular localization, and surrounding microenvironmental conditions.

Structurally, human SQSTM1/p62 is a 440-amino acid multidomain protein organized to bridge ubiquitinated cargoes directly to the degradation machinery while providing an assembly platform for vital cellular signaling cascades. Its architecture features an N-terminal Phox and Bem1 domain that drives homotypic oligomerization into cytoplasmic bodies and interacts with atypical protein kinase C, MEK5, ERK1, and NBR1 to facilitate partner recruitment. Adjacent modules include a ZZ-type zinc finger domain that recognizes client proteins bearing N-terminal arginylated motifs and interacts with receptor-interacting protein 1 during TNF-alpha-associated NF-kappa-B signaling. Additionally, the protein incorporates a TRAF6-binding sequence that recruits TNF receptor-associated factor 6 to drive K63-linked ubiquitination, an LC3-interacting region that docks directly to LC3 and GABARAP family proteins on nascent autophagosomal membranes, a KEAP1-interacting region that directly engages the Kelch domain of KEAP1, and a C-terminal ubiquitin-associated domain responsible for binding polyubiquitinated cellular cargoes.

The function of SQSTM1/p62 is dynamically tuned through a complex network of RNA-based controls and post-translational modifications that alter domain accessibility, condensation status, and binding partner selection. At the transcript level, N6-methyladenosine modifications promote messenger RNA stability through binding by the reader protein YTHDC1, whereas small vault RNAs transcribed by RNA polymerase III bind the ZZ domain to impair oligomerization and weaken autophagic LC3 engagement. MicroRNAs such as miR-183-5p and miR-181a downregulate SQSTM1/p62 through direct 3-prime untranslated region interactions, while circular RNAs and long non-coding RNAs such as DEPDC1-AS1 modulate expression by sponging inhibitory microRNAs. Post-translational modifications further direct SQSTM1/p62 behavior, encompassing phosphorylation at Ser349, Ser403, and Ser409, along with Ser293, Ser294, Thr138, Ser207, Thr269, and Ser272. Ubiquitination by KEAP1-Cullin3 at Lys420 or by TRIM21 at Lys7, acetylation at Lys264, Lys295, Lys420, and Lys435 by enzymes including TIP60 and hMOF, and palmitoylation at Cys289 and Cys290 by ZDHHC19 dynamically govern protein stability, trafficking, and nuclear translocation.

Through these modular interactions, SQSTM1/p62 governs diverse signaling axes that link selective degradation to stress adaptation and cellular survival. Under homeostatic physiological conditions, the interaction between LC3 and SQSTM1/p62 drives the autophagic sequestration and lysosomal breakdown of ubiquitinated protein aggregates, damaged mitochondria via mitophagy, and intracellular pathogens. In contrast, under metabolic stress or impaired autophagic flux, SQSTM1/p62 accumulates and interacts competitively with the Kelch domain of KEAP1, an E3 ubiquitin ligase substrate adaptor that normally marks NRF2 for proteasomal degradation. Phosphorylation of SQSTM1/p62 at Ser349 markedly increases its affinity for KEAP1, displacing NRF2 and promoting its nuclear translocation to activate antioxidant response element genes including NQO1, HMOX1, and glutathione biosynthetic enzymes. This non-canonical activation relieves oxidative stress but simultaneously shields malignant cells from oxidative injury, thereby conferring resistance against chemotherapeutic regimens.

Beyond redox adaptation, SQSTM1/p62 organizes critical inflammatory, nutrient-sensing, and cell-death cascades that dictate tumor cell fate. Interaction with TRAF6 through the TRAF6-binding sequence promotes K63-linked polyubiquitination, stimulating the TAK1 and IKK-beta kinase complex to trigger nuclear translocation of NF-kappa-B and induce genes driving survival, cytokine release, invasion, and angiogenesis. In amino acid sensing, SQSTM1/p62 interacts with Rag GTPases to recruit mTORC1 to lysosomal membranes, a process further enhanced by TRAF2-mediated K63-linked ubiquitination at Lys420, supporting anabolic metabolism while simultaneously dampening autophagy. In extrinsic apoptotic signaling, ubiquitinated caspase-8 clusters within SQSTM1/p62-positive cytoplasmic foci to facilitate caspase-8 activation and programmed cell death, while caspase-8 can reciprocally cleave SQSTM1/p62 to modulate downstream signaling. Furthermore, SQSTM1/p62 relocalizes with DDX6 to form processing bodies that sequester PYCARD to facilitate NLRP3 inflammasome assembly, interacts with AXIN-STK11-AMPK complexes during metabolic energy stress, and facilitates the autophagic degradation of ATP citrate lyase to remodel de novo lipid biosynthesis.

In solid malignancies, the biological consequences of SQSTM1/p62 dysregulation diverge sharply depending on oncogenic drivers and tissue context. In preneoplastic lesions and early carcinogenesis, SQSTM1/p62-dependent selective autophagy operates as a tumor-suppressive mechanism by removing damaged mitochondria, restricting toxic reactive oxygen species, and preserving genomic integrity. However, when autophagic clearance is defective, persistent intracellular accumulation of SQSTM1/p62 sustains stressed tumor-initiating cells and drives malignancy. In hepatocellular carcinoma, chronic SQSTM1/p62 accumulation hyperactivates the non-canonical KEAP1-NRF2 pathway, suppresses ferroptotic cell death, and redirects glutamine metabolism toward glutathione production to support rapid proliferation. In KRAS-driven lung cancer, the protein is essential for NF-kappa-B activation and tumor initiation, while intersecting with NRBF2 and the NRF2-ATF6 axis.

The influence of SQSTM1/p62 extends beyond cancer cell-autonomous pathways into the surrounding tumor microenvironment, where it modulates stromal metabolism, fibroblast activation, and local immune responses. In prostate cancer-associated stromal fibroblasts, loss of SQSTM1/p62 reduces glucose and glutamine consumption, depletes glutathione synthesis, elevates reactive oxygen species, and stimulates autocrine and paracrine IL-6 release that accelerates tumor aggressiveness. Stroma-specific SQSTM1/p62 deficiency also upregulates ATF4, shifting glucose metabolism toward asparagine production to fuel neighboring epithelial tumor cells, while intact SQSTM1/p62 maintains cancer-associated fibroblast expression signatures through interactions with CSL and RBPJk. In the immune compartment, SQSTM1/p62 expression correlates with altered immune infiltration in breast cancer and regulates macrophage polarization in renal cell carcinoma. Selective autophagic degradation pathways involving chromatin regulator PBRM1 and transcription factor CEBPB further alter the phenotypic balance between M1-like and M2-like tumor-associated macrophages, ultimately governing cytotoxic CD8-positive T-cell infiltration within the tumor bed.

SQSTM1/p62 also influences non-canonical genome stability networks by functioning as an adaptive regulatory node in eukaryotic DNA damage responses. Following oxidative or alkylating DNA damage, SQSTM1/p62 undergoes acetylation at Lys264 and translocates into the nucleus, where it binds directly to the apurinic/apyrimidinic endonuclease APE1, enhancing its enzymatic activity and promoting base excision repair. Conversely, under conditions of defective autophagic flux, pathologically elevated SQSTM1/p62 inhibits the ubiquitin ligase RNF168, preventing appropriate chromatin ubiquitination and blocking the recruitment of downstream repair factors BRCA1 and RAD51 to double-strand breaks. In parallel, SQSTM1/p62 promotes the proteasomal degradation of FLNA and RAD51, suppressing homologous recombination repair and shifting repair mechanisms toward error-prone non-homologous end joining. Nuclear ubiquitination and degradation of excess SQSTM1/p62 mediated by the E3 ligase adaptor SPOP restores homologous recombination, highlighting that tightly controlled SQSTM1/p62 clearance is indispensable for preventing genomic instability.

Given its prominent contributions to oncogenic signaling, metabolic adaptation, and chemoresistance, researchers have actively pursued pharmacological modulators of SQSTM1/p62, though chemical development remains in early preclinical stages. The small-molecule inhibitor XRK3F2 selectively targets the ZZ domain of SQSTM1/p62 with an IC50 of 4.6 micromolar, disrupting ZZ-dependent interactions, blocking TNF-alpha action in bone marrow stromal cells, and inducing apoptosis in multiple myeloma cells while impairing acute myeloid leukemia initiating capacity. Another small molecule, PTX80, acts as a specific antagonist exhibiting an IC50 of 31.18 nanomolar that successfully reduced tumor volume in HCT116 colorectal cancer mouse xenograft models. Furthermore, synthetic TRAF6 decoy peptides specifically abolish SQSTM1/p62 binding to TRAF6 and block NGF-dependent TrkA ubiquitination, and the small molecule K67 selectively targets the interaction between KEAP1 and Ser349-phosphorylated SQSTM1/p62 with an IC50 of 1.5 micromolar, restoring KEAP1-dependent NRF2 ubiquitination and reversing chemoresistance in hepatocellular carcinoma.

Despite these preliminary pharmacological proofs of concept, significant scientific obstacles must be resolved before SQSTM1/p62 inhibitors can advance into clinical oncology. Current compounds remain limited in chemical scaffold diversity, and it remains uncertain whether oncogenic signaling relies predominantly on an isolated domain or requires orchestrated cross-talk among PB1, ZZ, LIR, KIR, and UBA modules. A paramount safety challenge lies in selectively blunting tumor-promoting scaffolds without disrupting the essential homeostatic functions of SQSTM1/p62 in physiological autophagy, systemic redox defense, and metabolic balance. The authors emphasize that future clinical translation will require integrating structural biology with translational oncology to identify validated predictive biomarkers, such as baseline SQSTM1/p62 expression, post-translational modification profiles, autophagic competence, and co-occurring oncogenic mutations, to accurately stratify patients most likely to benefit from targeted therapeutic intervention.

Subject of Research: The dual molecular and therapeutic roles of selective autophagy receptor SQSTM1/p62 in cancer

Article Title: The mechanisms and roles of selective autophagy SQSTM1/p62 in cancer

Article References: Liu, Y., Xue, G., Liu, Y., Zhou, T., Cheng, B., Wu, J., Zhang, X., Sun, Z., Chu, P., & Song, J. (2026). The mechanisms and roles of selective autophagy SQSTM1/p62 in cancer. Frontiers in Cell and Developmental Biology, 14, Article 1992453. https://doi.org/10.3389/fcell.2026.1992453

Image Credits: AI Generated

DOI: 10.3389/fcell.2026.1992453

Keywords: autophagy, SQSTM1, p62, cancer biology, oncology, cellular stress, KEAP1-NRF2, mTORC1, signaling pathways, therapeutic targets, mechanisms, roles