SQSTM1

Overview

Sequestosome 1 (SQSTM1), widely recognized by its alias p62, is a multifunctional scaffold and signaling protein encoded by the SQSTM1 gene in humans. It is classified as an autophagy receptor and ubiquitin-binding adaptor, playing a central role at the intersection of the autophagy-lysosome pathway and the ubiquitin-proteasome system (UPS). Structurally, SQSTM1/p62 contains several key functional domains: an N-terminal PB1 domain for oligomerization and protein-protein interactions, a ZZ-type zinc finger domain, TRAF6-binding and KEAP1-interacting regions, a LC3-interacting region (LIR) that mediates direct binding to autophagosomal LC3 proteins, and a C-terminal ubiquitin-associated (UBA) domain that captures polyubiquitinated cargo destined for autophagic degradation. Through these domains, SQSTM1 physically bridges damaged or misfolded ubiquitinated proteins to the nascent autophagosome, enabling their selective clearance.

Beyond its canonical cargo-receptor function, SQSTM1 serves as a critical signaling node. It interacts with KEAP1 to regulate the nuclear factor erythroid 2-related factor 2 (NRF2) antioxidant pathway, participates in the AMPK/mTOR axis governing nutrient sensing and autophagy induction, and modulates inflammatory signaling. Because SQSTM1 is itself degraded during productive autophagy, its intracellular abundance is widely used as an inverse marker of autophagic flux: accumulation of p62 indicates impaired or blocked autophagy, while its reduction signals active autophagic degradation. This property makes SQSTM1 a key readout in mechanistic studies of autophagy across a broad range of disease contexts, from neurodegeneration and cardiac disease to cancer biology and acute organ injury.

Focus of Latest Publications

Mitophagy and Acute Organ Injury

Recent research has positioned SQSTM1 as a central readout in studies of mitophagy-mediated organ protection. In a model of septic acute kidney injury, nicotiflorin treatment in LPS-induced C57BL/6 mice restored the PINK1/Parkin mitophagy axis, as evidenced by increased expressions of PINK1, Parkin, and the LC3II/LC3I ratio alongside decreased p62 levels. This reduction in p62 was interpreted as evidence of restored mitophagic flux — damaged mitochondria being successfully tagged and cleared — thereby reducing oxidative stress and renal inflammation. Similarly, in a cardiac model of Friedreich's ataxia characterized by mitochondrial iron overload and lysosomal dysfunction, mitophagy impairment was directly evidenced by excessive accumulation of both p62 and Parkin proteins, establishing SQSTM1 accumulation as a hallmark of failed mitochondrial quality control in cardiomyopathic tissue.

Neurodegeneration: Alzheimer's and Parkinson's Disease

SQSTM1/p62 has emerged as a convergent marker in multiple neurodegenerative disease models. In a study of progressive cerebral amyloidosis and mitochondrial dysfunction, hippocampal mitochondria from 9-month-old transgenic rats showed elevated fission markers, nitrosative stress, and mitochondrial p62 accumulation — features absent in younger 3-month-old animals — suggesting that age-dependent autophagic failure and p62 buildup precede or accompany amyloid pathology. In an Alzheimer's disease mouse model, GRIN2B upregulation was accompanied by autophagic dysfunction characterized by an increased LC3B/LC3A ratio, elevated PINK1, and notably reduced p62, pointing to a complex, context-dependent dysregulation of autophagic flux rather than simple blockade. Treatment with β-Asarone, Tenuifolin, and YuanZhi Decoction in this model was associated with modulation of this GRIN2B-associated autophagy axis.

In a Parkinson's disease model, the H2S donor sulforaphane inhibited NLRP3 inflammasome activation by inducing mitochondrial autophagy, with effects on the LC3-II/I ratio and p62 dynamics reflecting modulation of mitophagic activity. This study highlighted a mechanistic link between mitophagy, SQSTM1, and the suppression of the NLRP3 inflammasome, positioning p62 at the interface of mitophagy and neuroinflammation. Separately, electroacupuncture was shown to ameliorate depressive-like behaviors in CUMS rats by enhancing autophagy — reflected in decreased p62 alongside an increased LC3-II/I ratio — and attenuating hippocampal neuroinflammation, mediated through the VEGF/Akt1/ERK signaling pathway.

Ischemic Stroke and Neuroprotection

In a cerebral ischemia-reperfusion model, the natural compound poliumoside was found to modulate autophagy by affecting both LC3B and SQSTM1 levels, alongside anti-apoptotic effects mediated through regulation of B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax). This study placed SQSTM1 within a broader neuroprotective program integrating mitochondrial function restoration, autophagy regulation, and apoptosis suppression following ischemic stroke injury.

Bone and Metabolic Disease

In osteoporosis research, betulinic acid (BA) was shown to increase autophagy in MC3T3-E1 osteoblasts treated with hydrogen peroxide — a model of oxidative stress-induced osteoblast injury — as confirmed by increased LC3b II and Beclin-1 expression and decreased P62 levels. The mechanism was linked to the AMPK-mTOR signaling pathway, identifying SQSTM1 as a downstream effector of this canonical autophagy regulatory axis and suggesting that promoting SQSTM1 clearance may support osteoblast survival in the context of Age-related osteogenic failure.

Cancer Biology and Proteostasis Stress

SQSTM1 has also been investigated in cancer biology, particularly in the context of therapeutic stress and proteostasis disruption. Transcriptomic profiling of polyploid giant cancer cells under therapeutic stress revealed strong upregulation of autophagy-related genes including SQSTM1 (P62), LC3, and LAMP1, and autophagy was demonstrated to be essential for the survival and function of these cells. This suggests that cancer cells co-opt SQSTM1-mediated selective autophagy as an adaptive survival mechanism under cytotoxic pressure.

In ovarian cancer research, p97/VCP was identified as a dual regulator of the UPS and autophagy. Chloroquine treatment — which blocks lysosomal acidification — significantly reduced p97/VCP levels while inducing pronounced accumulation of ubiquitinated proteins, p62, and LC3-II, consistent with impaired autophagic flux and disrupted proteasomal degradation. Complementary studies in uterine leiomyosarcoma cells demonstrated that bortezomib, a proteasome inhibitor, induced p62 accumulation alongside increased LC3B-II levels, interpreted as altered autophagic processing rather than canonical autophagy activation — a distinction highlighting the importance of distinguishing autophagic induction from productive flux when measuring p62 and LC3 markers.

Key Publications

• Jun Poliumoside alleviates oxidative stress and improves mitochondrial function to alleviate ischemic stroke injury. (European journal of pharmacology, 2026, PMID 42134761): "It also modulated autophagy by affecting Microtubule-associated proteins 1A/1B light chain 3B (LC3B) and Sequestosome 1 (SQSTM1), and exerted anti-apoptotic effects by regulating B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax)."
• May Autophagy is essential for survival and function of polyploid giant cancer cells under therapeutic stress. (Cancer letters, 2026, PMID 41833656): "Transcriptomic profiling revealed enrichment of metabolic and cytoskeletal pathways, with strong upregulation of autophagy-related genes, including SQSTM1 (P62), LC3, and LAMP1."
• May p97/VCP as a dual regulator of UPS and autophagy in ovarian cancer: a novel therapeutic target. (Journal of molecular histology, 2026, PMID 42185680): "In contrast, chloroquine treatment significantly reduced p97/VCP levels while inducing a pronounced accumulation of Ub, p62, and LC3-II (p < 0.05), consistent with impaired autophagic flux and disrupted proteasomal degradation."
• May β-Asarone, Tenuifolin, and YuanZhi Decoction Restore Cognitive Function and Modulate GRIN2B-Associated Autophagy in Alzheimer's Disease. (Neurochemical research, 2026, PMID 42171824): "GRIN2B upregulation in AD mice was accompanied by autophagic dysfunction (increased LC3B/LC3A ratio and PINK1, reduced p62) and mitochondrial stress."
• May Electroacupuncture Ameliorates Depressive-Like Behaviors by Enhancing Autophagy to Attenuate Hippocampal Neuroinflammation via the VEGF/AKT1/ERK Pathway in CUMS Rats. (Neurochemical research, 2026, PMID 42149321): "This was accompanied by enhanced autophagic activity (increased LC3-II/I ratio, decreased p62) and attenuated neuroinflammation (reduced IL-1β, TNF-α)."
• May Betulinic acid alleviates the inflammatory injury of osteoblasts in osteoporosis by augmenting autophagy via the AMPK-mTOR signaling pathway. (International journal of molecular medicine, 2026, PMID 42138188): "Administration of BA increased the autophagy of MC3T3-E1 cells treated with H2O2, which was confirmed by the increased expression levels of LC3b II and Beclin-1 and the decreased expression levels of P62."
• May Proteasome inhibition by bortezomib induces stress-response-mediated cytotoxicity in uterine leiomyosarcoma cells. (Biochemical and biophysical research communications, 2026, PMID 41861709): "Finally, autophagy-related analyses demonstrated increased LC3B-II levels accompanied by p62 accumulation, suggesting altered autophagic processing rather than simple activation of autophagy."
• Apr Mitochondrial iron overload is associated with lysosomal dysfunction-mediated mitophagy impairment in the heart of Friedreich's ataxia. (Mitochondrion, 2026, PMID 41628678): "the clearance of damaged or dysfunctional mitochondria (i.e., mitophagy) is disrupted, as evidenced by excessive accumulation of p62 and Parkin proteins."
• Apr Human in vitro and rodent in vivo models highlight progressive mitochondrial dysfunction as a starting point of cerebral amyloidosis. (Neurobiology of aging, 2026, PMID 41637762): "Similarly, hippocampal mitochondria fraction of 9-month-old Tg rats showed elevated fission markers, nitrosative stress, and mitochondrial p62 accumulation, which were absent in 3-month-old Tg animals."
• Apr The H2S donor sulforaphane inhibits NLRP3 inflammasome activation by inducing mitochondrial autophagy and mitigating CBS-H2S axis damage in in-vitro and in-vivo models of Parkinson's disease. (Bioorganic chemistry, 2026, PMID 41797134): "...increased the LC3-II/I ratio, and inhibited p62 degradation..."