The structure of proteins holds the key to their optimum functioning. Misfolding of proteins often renders them useless and the resulting aggregates are implicated in endoplasmic reticulum stress and the onset of several human diseases. Therefore, a robust system, spearheaded by unfolded protein response (UPR) is in place as a quality check. The unfolded proteins are cleared and marked for degradation. UPR pathway consists of multiple factors, such as the chaperone GRP78, and is often deregulated in cancers, thus presenting as an attractive target for therapy. Emerging evidence indicates epigenetic regulation of UPR with the involvement of non-coding RNAs, such as, microRNAs and long non-coding RNAs, as well as DNA methylation and histone modifications. Here, we provide an overview of UPR in tumorigenesis with a focus on mutual inter-regulatory relationship between UPR and non-coding RNAs. We also discuss the novel findings on transport of misfolded proteins in exosomes and the promising role of epigenetic drugs in modulation of UPR.

Over the past century, the development of advancements in hemophilia therapy has experienced unprecedented success, starting with virally contaminated blood product infusions and progressing to safe plasma-derived and recombinant factor replacements, non-factor based rebalancing agents, long-lasting gene therapies, and moving forward into an era of potentially curative gene editing. Hemophilia A (FVIII deficiency) and B (FIX deficiency) are rare, monogenic, congenital bleeding disorders caused by mutations in the F8 and F9 genes, respectively. These mutations, along with environmental and cellular stressors, result in the translation of misfolded FVIII or FIX proteins, leaving patients with hemophilia susceptible to spontaneous bleeding and hemophilic arthropathy. Misfolded FVIII or FIX proteins show reduced clotting activity, are more vulnerable to degradation, and contribute to cellular stress and immune activation. Hemophilia is diagnosed using a combination of functional and immunological assays to detect Factor VIII or FIX activity and protein levels, which are proportional to phenotype severity. Newer approaches to clinical management of hemophilia include intravenous half-life extended clotting factor preparations, subcutaneous non-factor treatments and three gene therapies approved by the U.S. Food and Drug Administration. Gene therapy provides longer-term, therapeutic factor levels without the need for clotting factor replacement prophylaxis. Ongoing research to further improve therapeutic options is focused on small molecule therapies such as molecular chaperones and protein stabilizers, as well as CRISPR/Cas9 gene editing tools with curative potential. In combination with innovative therapeutic strategies, it will remain critical to bolster patient adherence to treatments by advocating for patients to play an active role in making decisions about their health care.

Cancer appears to be a significant global public health concern and most prevalent leading cause of death worldwide. Delays in the diagnosis and treatment may lead to an increase in the prevalence of advanced-stage disease and death. Therefore, creating innovative diagnostic instruments and treatments that demonstrate high effectiveness is imperative. The majority of malignancies have dysfunction in the p53 pathway. In addition, p53 becomes dysfunctional and tends to undergo misfolding and aggregation, resulting in the creation of amyloid aggregates. Efforts are underway to investigate methods for reinstating the regular functioning and manifestation of p53. In this study, we have investigated Heat shock proteins (HSPs), which are molecular chaperones that play a significant role in various cellular processes such as intercellular transportation, formation or disintegration of complex protein, stabilisation or degradation of aggregated or misfolded proteins and protein folding. HSP40, also known as JDPs, are distinguished by their highly conserved J-domains. These domains facilitate the ability to bind to HSP70 and as a co-chaperone enhance the activity of ATPase. Emerging evidence indicates that HSP70/JDPs can influence the levels and/or functions of both wild-type and mutant p53. Only a small number of HSP40/JDPs, including C7, C2, B9, B1, A3, and DNAJA1, have been seen to influence the functions of both WT-p53 and Mut-p53. However, out of the sixteen members, only these handful are implicated in the advancement of cancer. Therefore, studying other HSP40/JDPs that are involved in the advancement of cancer and the activities of p53 (both mutant and wild type), together with their related processes, would enhance our understanding of how cancer progresses, we might potentially speed up the development of innovative treatments for cancer. It is expected that pharmacological molecules and their analogues that specifically target p53 aggregation might be utilised with other anticancer drugs to address the issue of p53 aggregation.

Protein misfolding and aggregation play a pivotal role in the development of neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's disease, and other related disorders. Proper protein folding is essential for cellular function, but due to the complexity of the folding process and external factors like genetic mutations, oxidative stress, and aging, misfolding is inevitable. These misfolded proteins often aggregate into toxic forms that disrupt cellular processes, leading to neuronal damage and cognitive decline. This chapter provides a comprehensive overview of molecular mechanisms behind protein misfolding, highlighting how these abnormal structures contribute to neurodegeneration. It also explores the role of the proteostasis network and its therapeutic potential in alleviating these processes. Focusing on multitarget therapeutic strategies, the chapter offers insights into promising approaches for addressing the root causes of neurodegenerative diseases while identifying key research gaps that could shape future treatment developments. By blending current knowledge with emerging therapeutic directions, this chapter provides a comprehensive and engaging perspective on combating the challenges of protein misfolding in neurodegeneration.

Cholesterol, produced by astrocytes, is vital for the formation and maintenance of synapse, highlighting the significance of lipid metabolism in neuronal health. Neural stem cells (NSCs) are versatile, self-renewing and capable of differentiating into neurons, astrocytes, and oligodendrocytes, playing a pivotal role in both embryonic development and adult neurogenesis. In the central nervous system (CNS), NSCs primarily reside in the subventricular zone (SVZ) and the sub-granular layer of the dentate gyrus, where they give rise to neural progenitors and subsequently to neurons and glial cells. Oligodendrocytes play a crucial role in the CNS function and myelin sheath formation, which is essential for rapid neuronal signal transmission. Astrocytes contribute to brain homeostasis by regulating lipid metabolism and providing metabolic support to neurons. Sphingolipids and phospholipids are integral to neural cell membrane structure and function, influencing processes such as neurogenesis, cell signaling, and synaptic plasticity. Furthermore, the ApoE4 allele impacts lipid metabolism, affecting the risk of neurodegenerative diseases. This paper explores the role of various cell types and lipids in the CNS, emphasizing the importance of lipid metabolism in maintaining neural function and the implications for neurodegenerative conditions.

Protein misfolding is a process in which an amino acid chain fails to attain its correct three-dimensional conformation, leading to structural abnormalities and functional impairment. This phenomenon plays a crucial role in various pathological conditions, including cancer, where it contributes to disease progression and cellular dysfunction. Cancer cells often secrete misfolded proteins, which actively interact with the tumor microenvironment (TME)-a complex network of stromal cells, immune cells, fibroblasts, and tumor cells-to influence key oncogenic processes. The consequences of protein misfolding extend beyond mere structural anomalies; they can drive tumorigenesis by enhancing cell proliferation, promoting metastasis, suppressing immune responses, and inducing chemoresistance. Given these critical implications, understanding the interplay between misfolded proteins and the TME offers valuable insights for therapeutic advancements. This chapter explores the molecular basis of protein misfolding, its role in modulating the TME, its impact on cancer progression, and emerging therapeutic strategies. Additionally, selected case studies are presented to highlight real-world applications of these concepts in cancer treatment and research.

Within the cellular milieu, protein molecules must fold into precise three-dimensional structures to attain functionality. Protein chains can assume many misfolded states during this critical process. Such errant configurations are unstable and can aggregate into toxic misfolded conformations. In protein misfolding disorders, polypeptides are folded in an aberrant manner, resulting in non-functional and often pathogenic states. Protein folding is fundamental to biological function, and disruption of the process can result in toxic aggregates, such as oligomers and amyloid fibrils, which are implicated in a variety of diseases, particularly neurodegenerative diseases such as Alzheimer's and Parkinson's. Here, we examine the delicate interplay of forces that determine the native conformation of proteins and how perturbations in this balance lead to disease. A critical aspect of our discussion is the cell's proteostasis network, a complex network of molecular chaperones and regulators responsible for regulating protein folding and maintaining the health of the cell. In this chapter, we discuss how intrinsic protein properties, post-translational modifications, and extrinsic environmental factors can destabilize proteins, thereby resulting in their misfolding. Several pathogenic mechanisms will be elucidated, including the progression from a misfolded protein to the development of disease phenotypes. Next, the chapter will present an overview of the current therapeutic approaches to mitigate the diseases caused by protein misfolding. Using the latest findings in clinical and experimental research, we will evaluate the therapeutic landscape, ranging from small-molecule inhibitors to chaperone-based therapies.

Viral fitness presents a complex challenge that requires a deep understanding of evolution and selection pressures. The swift emergence of mutations in viruses makes them ideal models for studying evolutionary dynamics. Recent advancements in biophysical methods and structural biology have facilitated insights into how these mutations influence evolutionary trajectories at the structural level. Computationally guided structural techniques are particularly valuable for analyzing the mutational landscape across all possible mutations in viral proteins under selection pressure. The virus often interacts via the receptor binding domain (RBD) of its surface protein with the receptor protein of the host cell. This binding is a key step for the viral entry in host cell and infection. In response, the host immune response or vaccines generate antibodies to neutralize the virus particles. This creates a competitive scenario where the viral surface protein competes for binding between host cell receptor and antibodies. The viral mutations supposedly evolve to effectively bind to host receptors while evading the antibody recognition. The differential binding affinity of the viral surface protein, preferably via RBD, between host receptor and antibodies may aid in defining the molecular level viral fitness function. The present chapter explores these dynamics through the lens of severe acute respiratory syndrome coronavirus 2 spike protein, binding to human angiotensin-converting enzyme 2 and circulating antibodies. Interestingly, this strategy utilized the wealth of protein structural data from cryo-electron microscopy and biochemical data on mutations.

Parkinson's disease (PD), a progressive neurodegenerative disorder, is primarily characterized by the accumulation of alpha-synuclein (α-syn) aggregates in the brain, leading to the neuronal dysfunction and degeneration. As a result, targeting α-syn aggregation is emerging as a promising therapeutic strategy for delaying or stopping disease progression. The present chapter tried to explore the progress made in the development of small molecule inhibitors in preventing or reversing the aggregation of α-syn. Overall, the chapter provides an overview of the mechanisms underlying α-syn misfolding and aggregation, and highlights potential small molecules inhibitors of α-syn aggregation with an update about their clinical trial studies. The chapter also provides current status of clinical trials of these inhibitors. Furthermore, emerging strategies including combination therapies, multi-target approaches, and small molecule-based chaperone therapeutics that might enhance the efficacy of these small molecule inhibitors are discussed. Future directions are also highlighted, emphasizing the emerging potential of small molecule inhibitors in disease-modifying treatments for PD.

Protein misfolding is a fundamental biological process with profound implications for human health and disease. Typically, proteins assume precise three-dimensional structures to perform their functions, a process safeguarded by the proteostasis network, which comprises molecular chaperones, the ubiquitin-proteasome system (UPS), and autophagy. However, genetic mutations, oxidative stress, and environmental insults can disrupt folding, leading to the accumulation of non-functional or toxic conformations. In neurodegenerative diseases such as Huntington's disease (HD), Parkinson's disease (PD), Alzheimer's disease (AD), Amyotrophic lateral Sclerosis (ALS), chronic misfolding results in toxic protein aggregates like amyloid-β, tau, and α-synuclein. These disrupt synaptic function, induce oxidative and nitrosative stress, and trigger apoptosis, ultimately leading to progressive neuronal loss. Dysregulation of the unfolded protein response (UPR) and weakened proteostasis with aging exacerbate disease pathology. In contrast, cancer cells utilize protein misfolding to enhance their survival and progression. Misfolded oncoproteins, such as mutant p53, not only evade degradation but also acquire oncogenic properties. Tumor cells hijack the UPR and chaperone networks, upregulate heat shock proteins, and manipulate oxidative stress responses to withstand hypoxia, nutrient deprivation, and rapid proliferation. Cancer stem cells (CSCs) further adapt to proteotoxic stress, contributing to tumor heterogeneity, therapy resistance, and immune evasion. The dual role of protein misfolding, driving degeneration in neurons while supporting proliferation in tumors, underscores its centrality in disease biology. Future research should focus on identifying early biomarkers of proteostasis imbalance and exploiting shared molecular pathways for the development of novel therapeutic interventions.

Proteins misfolding in neurodegenerative disorders pose a significant challenge to human health and this necessitates a deeper understanding of the fundamental molecular mechanisms. Molecular chaperones are a diverse group of specialized proteins, which are extensively involved in maintaining cellular protein homeostasis and thus preventing aggregation of misfolded proteins. Pathological advancement in several neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD) is characterized by the rampant accretion of misfolded proteins due to chaperonic failure, leading to progressive neuronal dysfunctioning and eventually cell death. Such as in AD, Hsp70 and Hsp90 chaperones are known to interact with β-amyloid and tau proteins, thus preventing their subsequent aggregation with concomitant refolding into native conformations. In PD, chaperones are involved in assisting mitigation of α-Syn misfolding and aggregation, thereby maintaining the normal neuronal functions and their viability. Similarly in HD, chaperones modulate aberrant misfolding of huntingtin protein and its aggregation, thus highlighting prospective therapeutic targets for disease intervention. Nevertheless, further investigating and understanding the explicit roles of chaperones in modulating several protein misfolding diseases holds potential for the development of novel therapeutic approaches. Moreover, targeting such specialized chaperone machinery in restoring protein homeostasis and alleviating subsequent protein aggregation could be considered as a promising approach in managing neurodegenerative disorders.

Alzheimer's disease is a prominent neurological disorder, which leads to progressive dementia. The microtubule-associated protein Tau is considered one of the major causes of Alzheimer's disease. Hyper-phosphorylation of Tau is considered to be closely associated with the generation of Tau pathology. CDK5 is one of the prominent neuronal kinases, under normal conditions, the activity of CDK5 is regulated by p35 protein. The stress conditions result in calpain-mediated proteolytic cleavage of p35 leading to the generation of p25 and p10. CDK5/p25 complex is reported to have a relatively more half-life which causes hyperphosphorylation of many proteins leading to neurotoxicity but the role of p10 is still needed to be explored. In the present review, we hypothesized the role of p10 as CDK5/p25 inhibitor. The current research has demonstrated that p10 provides survival signals to cells. In the current scenario, several CDK5 inhibitors commonly have a drawback of non-specificity. Here based on complied studies we hypothesize that the p10 could have the potency to inhibit the activity of CDK5, which ultimately downregulate the hyperphosphorylation of Tau. Thus reducing the levels of phospho-Tau p10 could emerge as a novel therapeutic peptide against Alzheimer's disease. The proposed hypothesis would open new gates for research in the field of Alzheimer's and further would bring a new ray of hope for the disease.

Solid tumors are characterized by chaotic architecture and abnormal vasculature, which trigger rapid cell proliferation leading to steep oxygen gradients, and render the tumor core highly hypoxic or anoxic. These hypoxic regions within a tumor profoundly drive cancer progression by stabilizing key transcription factors, Hypoxia-Inducible Factors, HIF-1 and HIF-2. In addition to the well-established HIF pathways, hypoxic areas in tumors are being increasingly examined for their capacity to disrupt proteostasis, specifically influencing oxygen-dependent protein folding in the endoplasmic reticulum. Hypoxia acts as a key stressor, leading to the accumulation of misfolded proteins, triggering Unfolded Protein Response as a compensatory mechanism, mediated by the three main ER sensors: PKR-like ER kinase, Inositol-Requiring enzyme 1, and Activating Transcription factor 6. In a healthy cell, UPR typically seeks to induce cell death, reestablishing cellular equilibrium. Cancer cells subvert this response by utilizing it to their advantage, enhancing metabolic flexibility, evading immune surveillance, and establishing resistance. There is growing evidence that these hypoxia-induced misfolded proteins contribute to the progression of tumors by causing genomic instability and dysregulating oncogenic signaling. This chapter details how hypoxia regulates protein misfolding, leading to cancer cell adaptation, and outlines relevant therapeutic targets.

Design of nanobodies have emerged as a new trend in antibody engineering, leveraging their unique properties including high stability, solubility, and the ability to bind to challenging targets such as membrane proteins. The application of computational strategies is pivotal for refining the efficacy of protein binders like nanobodies by broadening the sequence diversity, forecasting and bolstering their binding potency, selectivity, and overall performance. Recent advancements in computational techniques, such as machine learning algorithms and physics-based molecular modeling have significantly improved the design and development of nanobodies. These techniques allow for the precise modeling of nanobody-target interactions, enabling the identification of key residues responsible for binding and the prediction of potential conformational changes. In this study, five parental nanobodies binding to GPCRs and transporters were first used as template to create in silico nanobody libraries with the SCHEMA algorithm. Then, their binding potential and function to GPCRs or transporters were predicted by pre-trained machine learning models. The sequences above a threshold were processed with Rosetta and AlphaFold2 for 3D structural predictions. To further identify optimal conformations of specific nanobodies theoretically binding to 5-HT1AR or SERT, protein-protein docking by RosettaDock were performed. Finally, based on these model complexes, new nanobodies were redesigned, resulting in 21 and 18 candidates with enhanced binding to 5-HT1AR and SERT, respectively.

Alzheimer's disease (AD), among the diseases associated with dementia, is the most prevalent. It has been estimated that over 55 million people older than 65 years-old are living with dementia worldwide. Two-thirds of the AD population are women. It is estimated that by 2050 there will be 139 million people with dementia. AD is a neurodegenerative, progressive and irreversible process, affecting the patient's daily life activities. The pathological neurodegenerative process of AD begins 15-20 years before the appearance of the first clinical symptoms. The histopathological analysis reveals the presence of neurofibrillary tangles (NFTs) and neuritic plaques [1] the main hallmarks of AD. In this work, we are describing the NFTs that are made up of paired helical filaments of tau protein, which undergo post-translational modifications such as hyperphosphorylation and truncation, favoring conformational changes of the molecule. The most relevant information about the pathological processing of the tau protein is presented, focusing on the truncation at Glu391 (minimal filament nucleus, PHF-core) as a pathological inducing event of the tau protein and as an early biomarker of AD. Based on reports and our evidence, we suggest that the hyperphosphorylated tau protein participates as the neuroprotective event against this highly toxic PHF-core.

Neuraminidases (NAs) are glycoside hydrolase enzymes pivotal in carbohydrate metabolism, ubiquitously present in viruses, bacteria, fungi, and mammals. These enzymes catalyze the cleavage of terminal sialic acid residues from glycoproteins and glycolipids, impacting various biological processes, including pathogen infections and cancer cell proliferation. In our study, we employed advanced in silico strategies to repurpose existing drugs, aiming to provide a rapid response to health emergencies posed by multi-drug-resistant bacteria and fungi, as well as expanding the arsenal of antiviral therapies. Phylogenetic and structural superimposition analyses revealed four principal NA clusters, grouping viral, bacterial, fungal, and metazoa NAs. Comprehensive sequence and structural analyses identified three conserved binding regions across diverse species. The first binding region, observed in NAs crystallized with 23 different small molecules from viruses, fungi, bacteria, and metazoa, consists of three contact points hosting a basic RR dipeptide or RRN tripeptide, a basic/acidic R[E/D] dipeptide, and a basic/aromatic RY dipeptide involved in substrate/inhibitors binding. A second binding pocket was highlighted by comparing a group of NAs sampled from metazoa, fungi, and bacteria, crystallized in complex with 4 small molecules. The third binding pocket was proposed based on a fungal NA crystallized in complex with 1 small molecule. These identified binding pockets are proposed for being targettable by selective inhibitors of species-specific NAs, suggesting new avenues for anti-infective and anticancer strategies.

The concept of tumors as prion-like diseases similar to neurodegenerative disorders has gained attraction in recent years. p53, the most well-known tumor suppressor, has been extensively studied for its expression, mutations, and functions in various cancers. Recent findings reveal that p53 undergoes prion-like aggregation in tumors, leading to pathological amyloid fibril formation, functional alterations, and tumor progression. The mechanisms of p53 aggregation involve mutations, structural domains, isoforms, and external factors such as Zn² concentrations, pH, temperature, and chaperone abnormalities. While the role of p53 aggregation in tumors is increasingly recognized, controversies remain regarding its precise pathogenic mechanisms. This chapter reviews the structural features of p53 amyloid fibrils, its aggregation characteristics and effects, and the molecular mechanisms driving this phenomenon. Additionally, this chapter summarizes current therapeutic approaches targeting p53 aggregation and prion-like behavior, including small molecules and peptides designed to inhibit aggregation and restore p53's tumor suppressive function. By illuminating these aspects, this chapter aims to deepen our comprehension of how p53 aggregation disrupts its physiological functions. It also highlights the potential of targeting these aggregates as a novel therapeutic strategy in cancer treatment.

Variants in the ABCA4 gene are a fundamental cause of several inherited retinal degenerations (IRDs), including Stargardt macular dystrophy, retinitis pigmentosa, and cone-rod dystrophy. These three ABCA4-driven diseases are estimated to cause blindness in 1.4 million people worldwide. As a result, genetic testing of ABCA4 is increasingly common in clinical settings. Of the 4111 identified variants in ABCA4, 1668 are missense, of which 47 % are of unknown pathogenicity (variants of unknown significance, VUS). This genetic uncertainty leads to three fundamental problems: (i) for IRD patients with multiple unclassified ABCA4 mutations, it is impossible to predict which variant will cause disease in relatives who have not yet developed it; (ii) development of variant-specific therapies remains limited; and (iii) these variants cannot be used to predict disease prospectively, which is essential for life-planning decisions and for directing patients to new clinical trials. This chapter describes approaches to deciphering the impact of ABCA4 genetic variants of unknown significance (VUS) using a combination of in silico and in vitro analyses. By leveraging complementary fields-protein biochemistry and computational biology-to create a "sequence-structure-function" workflow, where in silico 3D protein structural analysis of ABCA4 sequence variants serves as a tool to predict disease severity and clinical pathogenicity in conjunction with first-line bioinformatic tools and functional analysis. This approach represents a helpful step forward in understanding how ABCA4 variants affect structure and function and in evaluating their potential to cause inherited retinal diseases.

Heat shock proteins (HSPs) are a conserved family of molecular chaperones that play a fundamental role in maintaining cellular homeostasis by facilitating protein folding, preventing aggregation, and mediating proteostasis under stress conditions. In cancer, HSPs are frequently overexpressed, contributing to tumor initiation, progression, metastasis, and therapeutic resistance. Their ability to stabilize oncoproteins, regulate apoptosis, and modulate immune responses makes them key players in tumorigenesis and promising therapeutic targets. This article comprehensively explores the classification and functional diversity of HSPs, highlighting their interactions with oncogenic pathways such as PI3K/AKT, MAPK, and p53. We discuss the dysregulation of prominent HSP families, including HSP27, HSP40, HSP60, HSP70, HSP90, and HSP110 across various cancer types, emphasizing their roles in promoting malignancy and modulating treatment responses. The chapter further elucidates how HSPs facilitate metabolic reprogramming in cancer cells, primarily through their interactions with key metabolic regulators, such as HIF-1α, c-Myc, and AKT, thereby sustaining the Warburg effect and promoting tumor cell survival. We examine their potential applications in precision oncology, including the development of HSP inhibitors, immunotherapies, and personalized treatment strategies. Additionally, we discuss novel therapeutic approaches, including chaperone-mediated autophagy modulation, HSP-based vaccines, and the integration of nanoparticle-mediated drug delivery systems. While HSP-targeted therapies offer significant promise, challenges such as drug resistance, toxicity, and compensatory upregulation of other chaperones remain formidable obstacles. Future research should focus on refining therapeutic selectivity, optimizing combination regimens, and utilizing advanced technologies, such as CRISPR-based gene editing and nanotechnology, to enhance treatment efficacy.

Tau, an intrinsically disordered protein associated with microtubule stabilization, is crucial for cellular trafficking, and signaling pathways. Under pathological conditions, Tau undergoes post-translational modifications and structural changes, leading to its aggregation into neurofibrillary tangles (NFTs). The interactions between Tau and membrane lipids, including phospholipids like DOPC, DPPC, and proteins such as Apo E4, play a significant role in Tau aggregation. These interactions modulate Tau's structure, stabilization, and aggregation kinetics. Phospholipase C (PLC) and DEPC also influence Tau aggregation through signaling pathways and preservation of RNA integrity, respectively. Membrane lipid composition affects Tau-membrane interactions, which can promote Tau fibrillization and propagation, contributing to neurotoxicity in Alzheimer's disease (AD) and other Tauopathies. The disruption of lipid homeostasis by Apo E4, alterations in membrane fluidity and integrity by DPPC, and the influence of phospholipids on BBB functionality are significant in understanding Tau pathology.

The unfolded protein response (UPR) refers to a cellular response mechanism that occurs in response to the accumulation of misfolded or incompletely folded proteins in the ER, that maintains proteostasis. While the major aim of UPR is to restrain cell homeostasis, prolonged stages results in apoptosis. The oncogenic circumstances are typically ER stressors, and UPR activation encourages the oncogenic transformation process, in which all UPR signaling branches support the development of tumors, angiogenesis, immune invasion, and resistance to chemotherapy. Proteomics is a high throughput, large-scale comprehensive study of proteins, their structures, and functions including their interactions with each other. Proteomics has now emerged as a very crucial and robust technique for biomarker discovery especially in diseases such as cancer. We summarize the use of proteomics techniques emphasizing the identification of UPR-related biomarkers by enabling the examination of protein-level alterations and modifications that propel UPR-mediated carcinogenesis. This could further be exploited for the early detection, prognosis, diagnosis and for therapeutic interventions for ER stress-mediated and UPR-mediated malignancies. This review elucidates the significant role and importance of different proteomic technologies and strategies in revealing UPR-mediated pathways in cancer, identifying main UPR effectors including GRP78, p53, PERK, IRE1α, and ATF6, and examines their potential as biomarkers for different cancer types. Integrating proteomic data with systems biology and machine learning techniques would further enhance our comprehension of UPR signaling in oncogenesis and facilitate the development of innovative tactics for personalized cancer therapy.