Heat shock proteins have been implicated in the process of carcinogenesis. HSPA14, a member of the heat shock protein family, remains poorly understood in terms of its significance and pathomechanisms in breast cancer.

We analyzed the expression levels of HSPA14 and its prognostic significance in breast cancer using TCGA data. TCGA data was used to investigate the association between HSPA14 expression and clinicopathological features in breast cancer patients. GSEA analysis was conducted to identify the biological function of HSPA14. Spearman's correlation analysis was performed to examine the correlation between HSPA14 expression and immune cell infiltration, as well as immune checkpoint genes. Single cell transcriptomic data from GSE114727 was utilized to calculate the expression of HSPA14 in different cell subpopulations. The data on HSPA14 levels and drug sensitivity were extracted from the CellMiner dataset. The mRNA expression of HSPA14 was validated through cell experiments.

HSPA14 expression is elevated in breast cancer, which is associated with poor overall survival. It can serve as a diagnostic biomarker for breast cancer patients. Pathway analysis revealed that HSPA14-associated differential genes are involved in cell cycle, apoptosis, cellular response to heat stress, and more. Additionally, HSPA14 expression is significantly correlated with the immune microenvironment. The expression of HSPA14 may also indicate drug sensitivity.

Our study elucidates the involvement of HSPA14 in tumorigenesis, particularly in modulating the immune response, shaping the immune microenvironment, and contributing to drug resistance, which are pivotal for the development of personalized breast cancer therapies.

Heat stress (HS) induces hypoxia and oxidative stress, reducing animal health and livestock production. Red blood cells (RBCs) are responsible for oxygen delivery, and are susceptible to HS. In this study, 12 healthy buffaloes with a similar body condition, lactation, and parity were raised under thermal-neutral (TN) conditions. After the collection of blood samples, buffaloes were randomly and equally divided into two groups. Six buffaloes underwent acute HS conditions for eight days (AHS group). Subsequently, these six AHS buffaloes were subjected to chronic HS conditions (AHS-CHS group). The other six TN buffaloes were raised under chronic HS conditions (CHS group). RBCs were isolated for data-independent acquisition-based proteomics to identify differentially expressed proteins involved in the HS response. Results showed that blood clotting factors, complements, immunoglobulins, and vasoconstriction proteins in RBCs were consistently decreased under the three types of HS conditions (AHS, AHS-CHS, and CHS). Moreover, the immunity of buffaloes experiencing AHS (AHS and AHS-CHS) was severely decreased when compared to those subjected to CHS. Due to high heat sensitivity of RBCs, AHS conditions should be avoided for dairy buffaloes in summer.

Nowadays, photodynamic therapy (PDT) offers a non-invasive tumor treatment with high safety profiles and minimal side effects, implying a promising clinical application for patients with malignant tumors. However, the lack of efficacy in metastasis and recurrence still notably limits its application. To solve this problem, one promising strategy is to improve the immune response activated by PDT. Unfortunately, tumor cells derived PGE2 could create immunosuppressive microenvironments and impair the function of multiple immune cells, leading to a failure of immune system activation. Moreover, our research revealed the up-regulation of Ptgs2 in tumor cells after the PDT process, which is associated with a series of pro-tumor effects, including proliferation, invasion, metastasis, apoptotic resistance, and immune evasion. Consequently, controlling the PGE2 surge induced by PDT is crucial for optimizing the efficacy of photo-immunotherapy. Therefore, we combined the regulation of the COX2-PGE2 axis with PDT. The addition of COX inhibitors (COX-Is) could improve the efficiency of PDT, reduce the immunosuppressive effect of PGE2, and help dying tumor cells activate the immune system. Herein, a tumor-targeted nano-delivery platform (FI@T-Lipo) was developed using advanced microfluidic technology. FI@T-Lipo based PDT showed a systemic therapeutic effect in triple negative breast cancer through reclaiming the anti-tumor effect of the immune system under COX2-PGE2 blockage. In a word, we developed an in-situ tumor vaccination strategy based on COX-Is enhanced PDT, which could alleviate intra-tumoral immune suppression and boost immune system activation. Our study offers a promising modality for advancing clinical treatment strategies for metastatic malignant tumors.

Lung cancer represents one of the most lethal malignancies, characterized by the highest incidence and mortality rates globally. Cisplatin-based chemotherapy exerts powerful anti-tumor activities in lung cancer, whereas its clinical application was limited due to the severe side effects. Dihydrotanshinone I (DHTS), a root extract from Salvia miltiorrhiza, exhibits diverse biological functions, encompassing liver protection, anti-inflammatory properties, promotion of osteoclast differentiation, and induction of apoptosis in tumor cells. DHTS exerts anti-tumor effects in various cancers, however, its biological functions in lung cancer are largely unknown. We demonstrated that DHTS synergistically increased the tumor suppressive effects of cisplatin in lung cancer cells by activating reactive oxygen species (ROS)-mediated endoplasmic reticulum stress (ER stress) and c-Jun N-terminal kinase (JNK) signaling pathways, both in vitro and in vivo. Additionally, DHTS induced excessive ROS accumulation by inhibiting the expression of Heat Shock Proteins 60 (HSPD1). Silencing HSPD1 augmented the anti-tumor effects of DHTS in lung cancer cells, primarily through the stimulation of ROS-mediated ER stress and JNK pathways. Our study suggests that DHTS possesses druggable potential, and combined therapy with DHTS and cisplatin may be a promising therapeutic strategy for certain lung cancer patients.

Therapy resistance is a major barrier to achieving a cure in cancer patients, often resulting in relapses and mortality. Heat shock proteins (HSPs) are a group of evolutionarily conserved proteins that play a prominent role in the progression of cancer and drug resistance. HSP synthesis is upregulated in cancer cells, facilitating adaptation to various tumor microenvironment (TME) stressors, including nutrient deprivation, exposure to DNA-damaging agents, hypoxia, and immune responses. In this review, we present background information about HSP-mediated cancer therapy resistance. Within this context, we emphasize recent progress in the understanding of HSP machinery, exploring the therapeutic potential of HSPs in cancer treatment.

Hyperthermia has emerged as a popular treatment option due to its high efficacy and seamless integration with other therapeutic approaches. To enhance treatment outcomes, hydrogels loaded with photothermal agents and activated by near-infrared (NIR) light for localized tumor therapy have attracted considerable attention. This approach minimizes drug dosage and mitigates the adverse effects of systemic drug delivery on healthy tissues. However, a challenge arises when NIR light sources inadvertently expose hydrogels loaded with high concentrations of photothermal agents, potentially causing localized overheating. Such overheating may trigger issues like inflammation, severe burns, and tissue crusting. To address this issue, the water in traditional hydrogels was substituted with the phase change material poly(ethylene glycol) (PEG), creating a phase change composite gel. This gel utilized PEG 2 M (PEG with a molecular weight of approximately 2,000,000 g/mol) as the gel scaffold and PEG 1.5 K (PEG with a molecular weight of approximately 1,500 g/mol) as the gel medium. Polydopamine modified with folic acid (PDA-FA) and MOF-199 loaded with 2, 2'-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride (AIPH@MOF-199) were uniformly dispersed throughout the gel. Experimental results have demonstratedthat this system can extend the duration of photothermal therapy while effectively avoiding localized overheating. Additionally, it synergizes well with thermodynamic therapy.

The upregulation of serpin family B member 5 (SERPINB5) has been linked to the progression of rectal cancer. However, the specific roles and underlying mechanisms of SERPINB5 in rectal cancer are not fully understood.

To investigate the roles and mechanisms of SERPINB5 in rectal cancer.

SERPINB5 protein level in rectal cancer tissues and cell lines was measured through western blot analysis. SW480 cells were transfected with pcDNA-SERPINB5 or short-hairpin RNA targeting SERPINB5 (sh-SERPINB5). Cell proliferation, invasion, and apoptosis were then evaluated. The interaction between SERPINB5 and heat shock protein 90 alpha class A member 1 (HSP90AA1) was confirmed through a co-immunoprecipitation assay. Subsequently, pcDNA-HSP90AA1 or sh-HSP90AA1 was transfected into SW480 cells, and cell progression was then detected. Moreover, rescue experiments were used to investigate the effect of the SERPINB5/HSP90AA1 axis on rectal cancer progression. Additionally, sh-SERPINB5-transfected SW480 cells were implanted into nude mice, and xenograft tumor growth was then evaluated.

SERPINB5 was prominently upregulated in rectal cancer tissues and cells. SERPINB5 overexpression increased SW480 cell proliferation and invasion while reducing apoptosis. In contrast, SERPINB5 knockdown had the opposite effects. Moreover, SERPINB5 could interact with HSP90AA1 and promote HSP90AA1 expression in SW480 cells. HSP90AA1 overexpression facilitated SW480 cell proliferation and invasion and restrained apoptosis. By contrast, HSP90AA1 knockdown suppressed cell progression. The upregulation of HSP90AA1 reversed the SERPINB5 silencing-mediated inhibition of SW480 cell progression. Additionally, SERPINB5 knockdown retarded the growth of rectal cancer tumors in vivo.

SERPINB5 knockdown inhibited rectal cancer cell proliferation and invasion and retarded xenograft tumor growth by inhibiting HSP90AA1 expression.

Molecular chaperones, a class of complex client regulatory systems, play significant roles in the prevention of protein misfolding and abnormal aggregation, the modulation of protein homeostasis, and the protection of cells from damage under constantly changing environmental conditions. As the understanding of the biological mechanisms of molecular chaperones has increased, their link with the occurrence and progression of disease has suggested that these proteins are promising targets for therapeutic intervention, drawing intensive interest. Here, we review recent advances in determining the structures of molecular chaperones and heat shock protein 90 (HSP90) chaperone system complexes. We also describe the features of molecular chaperones and shed light on the complicated regulatory mechanism that operates through interactions with various co-chaperones in molecular chaperone cycles. In addition, how molecular chaperones affect diseases by regulating pathogenic proteins has been thoroughly analyzed. Furthermore, we focus on molecular chaperones to systematically discuss recent clinical advances and various drug design strategies in the preclinical stage. Recent studies have identified a variety of novel regulatory strategies targeting molecular chaperone systems with compounds that act through different mechanisms from those of traditional inhibitors. Therefore, as more novel design strategies are developed, targeting molecular chaperones will significantly contribute to the discovery of new potential drugs.

One of the leading causes of mortality for women is gynecologic cancer (GC). Numerous molecules (tumor suppressor genes or oncogenes) are involved in this form of cancer's invasion, metastasis, tumorigenic process, and therapy resistance. Currently, there is a shortage of efficient methods to eliminate these diseases, hence it is crucial to carry out more extensive studies on GCs. Novel pharmaceuticals are required to surmount this predicament. Highly conserved molecular chaperon, heat shock protein (HSP) 90, is essential for the maturation of recently produced polypeptides and offers a refuge for misfolding or denatured proteins to be turned around. In cancer, the client proteins of HSP90 play a role in the entire process of oncogenesis, which is linked to all the characteristic features of cancer. In this study, we explore the various functions of HSPs in GC progression. We also discuss their potential as promising targets for pharmacological therapy.

The prognostic value of negative regulators of ferroptosis in patients with colorectal cancer (CRC) has not yet been fully elucidated. The present study performed a systematic in silico identification and selection of candidate negative regulators of ferroptosis using The Cancer Genome Atlas data cohort (n=367), followed by clinical validation through immunohistochemistry of samples from patients with CRC (n=166) and further in vitro evaluation. In silico analysis identified specific light-chain subunit of the cystine/glutamate antiporter, AIFM2, NFE2L2, FTH1, GLS2, glutathione peroxidase 4 (GPX4) and heat shock protein β-1 (HSPB1) genes as possible candidates. Furthermore, patients with high expression of GPX4 or HSPB1 exhibited significantly worse overall survival (OS) compared with those with low expression (P<0.01 for both). Immunohistochemical analysis revealed that both OS and recurrence-free survival (RFS) of patients with CRC and high GPX4 or HSPB1 expression were significantly worse compared with in patients with low expression (P<0.01 for all). Furthermore, multivariate analysis showed that high GPX4 and HSPB1 expression were independent risk factors for poor oncological outcome for OS and RFS (GPX4: RFS, P=0.03; HSPB1: OS, P=0.006 and RFS, P<0.0001). Moreover, the effects of GPX4 and HSPB1 small interfering RNAs on two CRC cell lines (DLD-1 and SW480) indicated that GPX4 and HSPB1 may exhibit important roles in attenuating the cytotoxic effect of 5-fluorouracil-based chemotherapy. In conclusion, the current study confirmed that GPX4 and HSPB1 may serve as substantial prognostic- and recurrence-predictive biomarkers in patients with CRC.

Exosomes as a unique drug delivery system provide a new choice for tumor therapy. However, the in vitro functionalization of exosomes and the process of circulating drug delivery can easily cause exosome degradation and drug loss, thus reducing the efficiency of drug delivery. In this work, based on the endocyto-fusion-exocytosis pathway of exosome formation, a multifunctional hyaluronic acid nanogel loaded with the antiangiogenic drug vatalanib and the near-infrared photothermal agent indocyanine green (ICG) was designed. Lysosome escape and photothermal therapy were combined to promote exosome production. Hyaluronic acid nanogels were endocytosed by tumor cells with CD44 mediation, forming intracellular vesicle-coated nanogels, which were subsequently degraded by hyaluronidase with high expression in tumor cells. Anti-angiogenic signals in intracellular vesicles were then delivered to vascular endothelial cells by exosomes through membrane fusion and exocytosis, which inhibited tumor angiogenesis to prevent tumor proliferation and metastasis. Cell experiments and tumor models demonstrate that our therapeutic strategy can achieve effective tumor inhibition.

Sepsis is a common systemic infectious disease followed by extremely high incidence and mortality with no effective treatment and clinical drugs. As a key mediator involved in infection and immunity, it has been reported that sepsis patients are accompanied by increased heat shock protein 70 (HSP70). Trained immunity is a novel innate immunity approach that can be activated by β-glucan to fight against sepsis. The mechanism of HSP70 activating trained macrophages against sepsis needs further elucidation. Trained immunity and sepsis models were established by β-glucan and LPS individually both in vivo and in vitro. We demonstrated that HSP70 was significantly upregulated in septic mice serum, and HSP70 could protect mice from sepsis by activating β-glucan-trained macrophages as an ideal secondary inducer via TLR2-NF-κB pathway. Additionally, the sepsis resistant effects of HSP70 could be blocked by its antibody. In summary, more than a molecular chaperone to maintain homeostasis, HSP70 could be an important trained immunity inducer to help the body fighting against sepsis, which provided new stimuli for trained immunity and novel therapeutic solutions for sepsis.

Despite remarkable clinical efficacy, little is known about the system-wide immunological alterations provoked by PD1 blockade. Dynamics of quantitative immune composition and functional repertoire during PD1 blockade could delineate cohort-specific patterns of treatment response and therapy-induced toxicity.

We longitudinally assessed therapy-induced effects on the immune system in fresh whole blood using flow cytometry-based cell quantifications, accompanied by analyses of effector properties of all major immune populations upon cell-type specific stimulations. 43 cancer patients undergoing PD1 blockade were recruited with assessments performed pre-treatment and before cycles 2/4/6, which resulted in the collection of more than 30,000 cytometric data values.

We observed no intrinsic immune pattern correlating with clinical outcome before PD1 blockade initiation, but cohort-specific immune alterations emerged during therapy. The most striking evolving changes in therapy responders were an increase in activated T and NK cell subsets, which showed high IFNγ and TNFα expression upon ex vivo stimulation. Patients affected by severe immune-related adverse events (s-irAE) presented with an analogously increased number of activated CD4 + and CD8 + T cells compared to patients with no/mild irAE, but lacked the functional divergences observed between responders versus non-responders. Instead, their monocytes showed discriminatory functional deficits with less IL10 production upon stimulation, which led to an abrogated inhibition of T cell proliferation in vitro and thus may account for the observed T cell expansion in patients with s-irAE.

Our holistic explorative approach allowed the delineation of clinically relevant cohorts by treatment-triggered immune changes, potentially enabling better patient stratification and further revealed new mechanistic insights into the pathogenesis of s-irAE.

DNAJC12 (DnaJ heat shock protein family (Hsp40) member C12) encodes a member of the molecular chaperone Hsp40/DnaJ family, which are important protein folding and proteostasis regulators. Its role as a biomarker has been studied for a limited number of cancer types. Objectives: Here, we sought to investigate the potential of DNAJC12 mRNA and protein expression as a prognostic and predictive biomarker for breast cancer (BC).

Using in silico analysis and data from immunohistochemistry analysis (IHC) of 292 samples from patients with primary BC, we determined the expression pattern and prognostic value of DNAJC12 mRNA and protein expression.

From online publicly available data, we were able to identify the transcripts of DNAJC12 as differentially expressed in patients with different clinicopathological characteristics, such as ER status (P < .001), PR status (P < .001), HER2 status (P < .010) and molecular subtype (P ⩽ .001). We also found DNAJC12 to be a potential prognostic predictor for overall survival, disease-free survival, and responsiveness to treatment; a low DNAJC12 mRNA expression is commonly associated with a worse prognosis. Using IHC analysis, we showed that low DNAJC12 protein-level expression is also associated with a worse prognosis in patients with all subtypes of BC and patients with Luminal BC, and its expression is significantly different between patients with different tumor size classifications (T1/T2 vs T3/T4; P = .013) or with different lymph node involvement (N0 vs N+; P = .005).

Our findings suggested a potential role for DNAJC12 as a prognostic and predictive biomarker for BC.

A nitric oxide (NO)-boosting molecular agent (CyHU) was developed for enhanced mild-temperature photothermal therapy (MPTT). This photothermal agent can specifically target mitochondria and efficiently produce NO, inhibiting adenosine triphosphate-dependent heat shock proteins, reversing tumor heat tolerance and ultimately achieving MPTT of cancer cells.

Despite the significant advancements in cancer research, innovative approaches are still needed to reduce tumor incidence, progression, and dissemination, as well as for prolonging patient survival. Currently, the development of cancer vaccines is gaining attention as a novel preventative and therapeutic strategy. Although the concept of cancer vaccination is not new, a limited number of vaccines have received approval for tumor therapy. Heat shock protein (HSP)-based vaccination represents a promising strategy that harnesses specific tumor antigens to activate immune responses. Exosomes (Exs) are highly heterogeneous bilayer vesicles capable of transporting various types of molecules through extracellular space. Compared with conventional anticancer drugs, exosomes exhibit low toxicity and good biocompatibility, and they can stimulate the immune system either directly or indirectly. Ex-based vaccines may elicit an antitumor immune response that generates memory cells capable of recognizing cancer antigens, thereby inhibiting disease progression. This paper reviews the potential applications of HSPs and exosomes in the prevention and treatment of solid tumors. Finally, we discuss the advantages of the extracellular exosomal heat shock protein (HSP-Ex) vaccine and future research directions aimed at optimizing heat shock protein-based cancer immunotherapy strategies.

Effective treatment of malignant tumors remains a thorny issue in current medicine. As a new type of anticancer strategy, photothermal therapy (PTT) has attracted tremendous attention due to its favorable therapeutic effectiveness, high spatial-temporal controllability, and low occurrence of side effects. However, the efficacy of PTT is significantly reduced due to the limited penetration of light and heat-induced overexpression of heat shock protein (Hsp). Herein, we propose an antitumor synergistic therapy that combines fiber-optic PTT and Hsp inhibitors. A rare-earth-doped optical fiber was used as the PTT actuator, and the Hsp inhibitor AT533 was loaded on the fiber surface by use of a hydrogel layer. PTT fibers can be guided to reach tumor lesions directly without being subject to the light penetration limit. The Hsp inhibitor can be released upon the softening of the hydrogel layer under photoheating to deactivate Hsp in the tumor and thus reduce the resistance of the tumor to PTT. This synergistic treatment enhanced the effect of PTT and successfully eradicated tumors in colorectal cancer (CRC) xenograft mouse models, providing a feasible way to realize antitumor and antirecurrence treatment. More importantly, the success of the synergistic treatment of PTT and Hsp inhibition opens new avenues for the development of multimodal and multitype synergistic fiber-optic treatments, which offer pronounced enhancement of therapeutic effectiveness for treating cancer.

Heat shock proteins (HSPs) are a kind of molecular chaperone that helps protein folding, which is closely related to cancer. However, the association between HSPs and clear cell renal clear cell carcinoma (ccRCC) is uncertain. We explored the prognostic value of HSP110, HSP90, HSP70 and HSP60 families in ccRCC and their role in tumor immune microenvironment. The data obtained from the Cancer Genome Atlas (TCGA) were applied to determine the differential expression of HSPs in normal tissues and ccRCC. We comprehensively analyzed the prognostic value of HSPs in ccRCC and constructed a prognostic signature. We further explored the differences of tumor immune microenvironment and targeted therapy based on the signature. Cell proliferation, invasion and metastasis were detected by CCK8 assay, wound healing and transwell. Three clusters were identified with differences in overall survival and tumor stage. 6-gene signature (HSPA8, HSP90B1, HSPA7, HSPA12B, HSPA4L, HSPA1L) was identified to predict ccRCC patients' prognosis. The signature was confirmed in the internal cohort. Survival analysis, receiver operating characteristic (ROC) curve, univariate and multivariate COX regression analysis demonstrated the accuracy and independence of signature. The expression of HSPA7, HSPA8 and HSP90B1 were validated with quantitative real-time PCR. Our signature played a pivotal role in predicting tumor immune microenvironment, immune checkpoint gene expression, drug sensitivity, and tumor mutational burden (TMB) in patients with ccRCC. Our cellular experiments confirmed HSPA7 promotes the proliferation, invasion and metastasis of ccCRC cells. The HSPs signature identified in this study could serve as potential biomarkers for predicting prognosis and treatment response in ccRCC patients. It may provide new ideas for the current research on targeted therapy and immunotherapy strategies for ccRCC patients.

HSP60 is implicated in many biological functions and plays a key role in maintaining oxidative stress and preserving mitochondrial integrity. Our previous study showed that HSP60 inhibits apoptosis. In this study, we further investigated the mechanism of apoptosis inhibition by HSP60. First, the CRISPR-Cas9 system was employed to establish the HSP60 knockout DF-1 cell line (DF-1-HSP60-KO), and the apoptosis level of DF-1-HSP60-KO cell line was assessed by flow cytometry and ELISA apoptosis kit. Then, the effect of knockdout of HSP60 on relevant apoptotic factors was assessed by Western blotting and RT-PCR analysis. The results showed that compared with the control DF-1 cells, HSP60 knockdout cells indicated significantly increased apoptosis rates, decreased Bax expression, and enhanced Caspase 3 expression. This suggests that the HSP60 knockout induces apoptosis by up-regulating Caspase 3 and down-regulating Bax expression. The structure of the HSP60 mitochondrial signal peptide (MIT) protein was predicted using Pymol software, which revealed that His amino acid at the 21st position affects its spatial structure. In addition, the transfection of HSP60 mutant protein (TB) into DF-1-HSP60-KO cells and induction with Bardoxolone MethyI significantly increased the apoptosis rates and reduced cell viability compared to the wild-type HSP60 group, inducing differential changes in genes such as Bax, Bak, and Bcl-2. Together, these findings suggest that the HSP60 MIT's His amino acid at site 21 modulates the levels of genes associated with the apoptosis signaling pathway, thereby inhibiting apoptosis. This study reveals the regulatory role of HSP60 in apoptosis through its mitochondrial signal peptide, which will have potential medical value.

Adult Schistosoma produces a large number of eggs that play essential roles in host pathology and disease dissemination. Consequently, understanding the mechanisms of sexual maturation and egg production may open a new avenue for controlling schistosomiasis. Here, we describe that Bantam miRNA and miR-1989 regulate Wnt signaling pathway by targeting Frizzled-5/7/9, which is involved in ovarian development and oviposition. Additionally, Frizzled-7 could cooperate with SjRho to maintain normal ovarian development and egg productions and SjRho may interact with Hsp60 to potentially support Frizzled-7 trafficking and signaling. Further in vivo inhibition of SjRho in mice model infected with Schistosoma results in a remarkable decrease in worm burden and egg productions. Our findings not only broaden the functions of Bantam miRNA and miR-1989 as well as Wnt signaling pathway, but also imply that interruption of Bantam/miR-1989-Frizzled-5/7/9-SjRho axis may serve as effective targets against schistosomiasis.

Parkinson's disease (PD) is characterized by the accumulation of misfolded α-synuclein (α-syn). Promoting the degradation of misfolded proteins has been shown to be an effective approach to alleviate PD. This review highlights the roles of specific heat shock proteins (HSPs) in modulating α-syn aggregation and neuronal survival. HSP27 prevents glycosylation-induced α-syn aggregation, disrupts copper ion interactions, inhibits mitochondrial apoptosis, and prevents dopaminergic neuronal cell death. HSP70 alleviates dopaminergic neuronal damage by promoting mitophagy and preventing neuronal apoptosis. HSC70 plays a critical role in chaperone-mediated autophagy and facilitates lysosomal degradation. GRP78 mitigates abnormal protein aggregation. The HSP70-HSP40-HSP110 system is capable of degrading α-syn amyloid fibers. Inhibition of HSP90 expression protects neurons. Further research should prioritize developing regulators of HSPs as treatments for PD. While HSPs offer promise in PD management, their complex roles necessitate cautious therapeutic development to harness their potential. Understanding the specific roles of different HSPs will be essential to developing effective therapies for α-syn clearance.

Glioblastoma (GBM) is an aggressive and lethal type of brain tumor in human adults. The standard of care offers minimal clinical benefit, and most GBM patients experience tumor recurrence after treatment. In recent years, significant advancements have been made in the development of novel immunotherapies or other therapeutic strategies that can overcome immunotherapy resistance in many advanced cancers. However, the benefit of immune-based treatments in GBM is limited because of the unique brain immune profiles, GBM cell heterogeneity, and immunosuppressive tumor microenvironment. In this review, we present a detailed overview of current immunotherapeutic strategies and discuss the challenges and potential molecular mechanisms underlying immunotherapy resistance in GBM. Furthermore, we provide an in-depth discussion regarding the strategies that can overcome immunotherapy resistance in GBM, which will likely require combination therapies.

Piperine has immunomodulatory and anti-inflammatory properties, and its potential in treating cervical cancer needs further exploration. Using data from The Cancer Genome Atlas (TCGA), we identified immune-related differentially expressed genes (IRDEGs) in cervical cancer. Predicted targets of piperine were compared with cervical cancer-associated genes from various databases. Protein-protein interaction (PPI) network analysis, enrichment of GO and KEGG pathways, and molecular docking were performed. Kaplan-Meier survival analysis was done to assess prognostic significance. In vitro and in vivo experiments were conducted to confirm findings. We obtained 403 IRDEGs, 125 piperine targets, and 7037 cervical cancer genes. PPI network analysis revealed potential targets and pathways regulated by piperine. Molecular docking showed good binding activity of piperine with specific targets. In vitro, piperine inhibited cervical cancer cell proliferation, migration, and invasion, and promoted apoptosis. In vivo, piperine suppressed tumor growth and downregulated expression of IL-1β and NLRP3 in tumor cells. Piperine also downregulated expression of IL-17A, IL-21, IL-22, and RORγt, and decreased the number of Th17 cells in tumor tissues. Piperine may inhibit cervical cancer progression through modulation of Th17 cell activation mediated by the NLRP3/IL-1β axis. Further studies are warranted to explore the potential of piperine as an immunomodulatory agent in cervical cancer treatment.

Hepatocellular carcinoma (HCC) is still one of the leading causes of tumor-related deaths. Accumulating evidence indicates that immunogenic cell death (ICD) could occur in tumor cells. However, ICD-related studies are limited in HCC. This study collected HCC RNA sequencing data from the Cancer Genome Atlas, International Cancer Genome Consortium, and Gene Expression Omnibus databases. R software was used to analyze the expression of ICD in HCC and to screen essential genes with prognostic value. qRT-PCR and WB determined the mRNA and protein expressions of hub gene. Cell viability assay, Clonal formation assay, and Live/dead staining assay were employed to determine the gene functions. After cross-analysis of differentially expressed genes (DEGs) and ICD-related genes (ICDRGs), 7 differentially expressed ICDRGs were identified in HCC. Of them, HSP90AA1, with the most excellent prognostic value in HCC, was selected, whose expression was also validated in public cohorts, cell lines, and clinical tissue samples. High HSP90AA1 expression indicated an inferior prognosis of HCC, and HSP90AA1 knockdown significantly suppressed cell viability and chemotherapy resistance of HCC. ICD-related gene HSP90AA1 was an unfavorable factor for HCC, and high HSP90AA1 expression contributed to tumor cell survival and chemotherapy resistance.

Obesity significantly impacts female reproductive health and increases the risk of gynecological tumors. However, the specific transcriptional changes that occur in the ovarian microenvironment during obesity-induced stress and the relationship between obesity and ovarian cancer remain unclear.

Our study investigated the single-cell landscape of the ovarian cortex in individuals with varying BMI levels by snRNA-seq, revealing weight-stage related cellular composition deviations and expression profile irregularities.

Using single-cell high-dimensional Weighted Gene Co-expression Network Analysis (hdWGCNA), we identified distinct obesity-related gene modules within various subpopulations of stroma cells and blood vascular endothelial cells. Notably, we observed a negative correlation between BMI and heat shock protein (HSP) family genes. Specifically, we found that HSPD1 might function as a potential regulator of ovarian carcinogenesis and progression under conditions of obesity, as supported by our co-analysis with data from three bulk RNA-seq ovarian cancer databases. Our findings suggested that lower expression of HSPD1 indicated a poorer prognosis for ovarian cancer.

Our study identified a cluster of genes in ovarian cells that are suppressed by obesity, including those belonging to HSP family genes. These findings provide valuable insights for investigating the link between obesity and ovarian diseases.

Mesenchymal stromal cells (MSCs) are considered a therapeutic approach for neurological diseases via extracellular vesicles (EVs). Modified EVs contain active components with enhanced therapeutic potential. In this study, we aimed to explore the role and underlying mechanism of EVs from MSCs preconditioned by NaHS (an Hydrogen sulfide donor) (H2S-EVs) in hypoxia-ischemia (HI) brain damage. Our results showed that H2S-EVs treatment via the non-invasive intranasal route in HI mice was able to reduce oxidative stress and mitochondrial dysfunction compared to EVs treatment. Mechanistic studies demonstrated that NaHS promoted nuclear factor erythroid-2 related factor 2 (Nrf2) expression in the cytoplasm by inducing Parkinson disease protein 7 (PARK7)-dependent disintegration of Nrf2/Keap-1 complex in MSCs. In particular, the free Nrf2 was loaded into the EVs as a result of its KFERQ motif being recognized by 70-kDa heat shock proteins and lysosomal-associated membrane protein 2A. Subsequently, H2S-EVs were internalized into neurons in the ipsilateral hemisphere, thus delivering abundant Nrf2 to accumulate in the mitochondria and remodeling mitochondrial function following H2S-EVs treatment in HI mice. Moreover, Nrf2 knockdown in MSCs remarkably impaired H2S-EVs-mediated therapeutic effects on HI mice. In brief, the present study for the first time demonstrated that H2S-modified MSCs significantly accumulated higher Nrf2 in EVs via upregulating PARK7 expression, revealing the mechanism through which antioxidant protein Nrf2 delivered by H2S-EVs protect against mitochondrial dysfunction in HI brain damage.

This study attempted to build a prostate cancer (PC) prognostic risk model with mitochondrial feature genes. PC-related MTGs were screened for Cox regression analyses, followed by establishing a prognostic model. Model validity was analyzed via survival analysis and receiver operating characteristic (ROC) curves, and model accuracy was validated in the GEO dataset. Combining risk score with clinical factors, the independence of the risk score was verified by using Cox analysis, followed by generating a nomogram. The Gleason score, microsatellite instability (MSI), immune microenvironment, and tumor mutation burden were analyzed in two risk groups. Finally, the prognostic feature genes were verified through a q-PCR test. Ten PC-associated MTGs were screened, and a prognostic model was built. Survival analysis and ROC curves illustrated that the model was a good predictor for the risk of PC. Cox regression analysis revealed that risk score acted as an independent prognostic factor. The Gleason score and MSI in the high-risk group were substantially higher than in the low-risk group. Levels of ESTIMATE Score, Immune Score, Stromal Score, immune cells, immune function, immune checkpoint, and immunopheno score of partial immune checkpoints in the high-risk group were significantly lower than in the low-risk group. Genes with the highest mutation frequencies in the two groups were SPOP, TTN, and TP53. The q-PCR results of the feature genes were consistent with the gene expression results in the database. The 10-gene model based on MTGs could accurately predict the prognosis of PC patients and their responses to immunotherapy.

Cancer is a global health challenge with rising incidence and mortality rates, posing significant concerns. The World Health Organization reports cancer as a leading cause of death worldwide, contributing to nearly one in six deaths. Cancer pathogenesis involves disruptions in cellular signaling pathways, resulting in uncontrolled cell growth and metastasis. Among emerging players in cancer biology, Transient Receptor Potential (TRP) channels, notably TRPV1, have garnered attention due to their altered expression in cancer cells and roles in tumorigenesis and progression. TRPV1, also known as the capsaicin receptor, is pivotal in cancer cell death and pain mediation, offering promise as a therapeutic target. Activation of TRPV1 triggers calcium influx and affects cell signaling linked to growth and death. Additionally, TRPV1 is implicated in cancer-induced pain and chemo-sensitivity, with upregulation observed in sensory neurons innervating oral cancers. Also, when capsaicin, a compound from chili peppers, interacts with TRPV1, it elicits a "hot" sensation and influences cancer processes through calcium influx. Understanding TRPV1's multifaceted roles in cancer may lead to novel therapeutic strategies for managing cancer-related symptoms and improving patient outcomes. The current review elucidates the comprehensive role of capsaicin in cancer therapy, particularly through the TRPV1 channel, highlighting its effects in various cells via different signaling pathways and discussing its limitations.

Reproductive cancers, such as ovarian, cervical, and endometrial carcinomas, have a poor prognosis in metastatic stages. Researchers are continuously seeking improved and safer methods to target cancer-related oncoproteins, addressing the limitations of current treatments, including their limited effectiveness, drug resistance, and off-target effects. Recent advancements in understanding the molecular mechanisms involved in the progress of reproductive cancers have provided valuable insights into potential targeted therapies. By engaging with oncoproteins and co-chaperones, heat-shock protein 90 (HSP90) regulates signaling networks and fixes protein folding errors in cancer cells. The potential of HSP90 inhibition as cancer-targeted treatments is underscored by the continuous discovery and testing of novel HSP90-targeted molecules for their antitumor properties in preclinical and clinical settings. Therefore, this study aims to shed light on the mechanism and recent research breakthroughs of HSP90, as well as provide an in-depth review of their therapeutic potential in reproductive cancers.

Mild photothermal therapy (MPTT) generates heat therapeutic effect at the temperature below 45 °C under near-infrared (NIR) irradiation, which has the advantages of controllable treatment efficacy, lower hyperthermia temperatures, reduced dosage, and minimized damage to surrounding tissues. Despite significant progress has been achieved in MPTT, it remains primarily in the stage of basic and clinical research and has not yet seen widespread clinical adoption. Herein, a comprehensive overview of the recent NIR MPTT development was provided, aiming to emphasize the mechanism and obstacles, summarize the used photothermal agents, and introduce various biomedical applications such as anti-tumor, wound healing, and vascular disease treatment. The challenges of MPTT were proposed with potential solutions, and the future development direction in MPTT was outlooked to enhance the prospects for clinical translation.

In advanced hepatocellular carcinoma (HCC) tissues, M2-like tumor-associated macrophages (TAMs) are in the majority and promotes HCC progression. Contrary to the pro-tumor effect of M2-like TAMs, M1-like TAMs account for a small proportion and have anti-tumor effects. Since TAMs can switch from one type to another, reprogramming TAMs may be an important treatment for HCC therapy. However, the mechanisms of phenotypic switch and reprogramming TAMs are still obscure. In this study, we analyzed differential genes in normal macrophages and TAMs, and found that loss of MANF in TAMs accompanied by high levels of downstream genes negatively regulated by MANF. MANF reprogrammed TAMs into M1 phenotype. Meanwhile, loss of MANF promoted HCC progression in HCC patients and mice HCC model, especially tumor neovascularization. Additionally, macrophages with MANF supplement suppressed HCC progression in mice, suggesting MANF supplement in macrophage was an effective treatment for HCC. Mechanistically, MANF enhanced the HSF1-HSP70-1 interaction, restricted HSF1 in the cytoplasm of macrophages, and decreased both mRNA and protein levels of HSP70-1, which in turn led to reprogramming TAMs, and suppressing neovascularization of HCC. Our study contributes to the exploration the mechanism of TAMs reprogramming, which may provide insights for future therapeutic exploitation of HCC neovascularization.

Colorectal cancer (CRC) is a common malignant tumor with high morbidity and mortality rates worldwide. Although surgical resection and adjuvant radiotherapy/chemotherapy are the mainstays of CRC treatment, the efficacy is unsatisfactory due to several limitations, including high drug resistance. Accordingly, there is a dire need for new drugs or a novel combination approach to treat this patient population. Herein, we found that cinnamaldehyde (CA) could exert an antitumor effect in HCT-116 cell lines. Target fishing, molecular imaging, and live-cell tracing using an alkynyl-CA probe revealed that the heat shock 60 kDa protein 1 (HSPD1) protein was the target of CA. The covalent binding of CA with HSPD1 altered its stability. Furthermore, our results demonstrated that CA could induce cell apoptosis by inhibiting the PI3K/Akt signaling pathway and enhanced anti-CRC activity both in vitro and in vivo. Meanwhile, CA combined with different chemotherapeutic agents was beneficial to patients resistant to anti-CRC drug therapy.

Heat shock proteins are essential molecular chaperones that play crucial roles in stabilizing protein structures, facilitating the repair or degradation of damaged proteins, and maintaining proteostasis and cellular functions. Extensive research has demonstrated that heat shock proteins are highly expressed in cancers and closely associated with tumorigenesis and progression. The "Hallmarks of Cancer" are the core features of cancer biology that collectively define a series of functional characteristics acquired by cells as they transition from a normal state to a state of tumor growth, including sustained proliferative signaling, evasion of growth suppressors, resistance to cell death, enabled replicative immortality, the induction of angiogenesis, and the activation of invasion and metastasis. The pivotal roles of heat shock proteins in modulating the hallmarks of cancer through the activation or inhibition of various signaling pathways has been well documented. Therefore, this review provides an overview of the roles of heat shock proteins in vital biological processes from the perspective of the hallmarks of cancer and summarizes the small-molecule inhibitors that target heat shock proteins to regulate various cancer hallmarks. Moreover, we further discuss combination therapy strategies involving heat shock proteins and promising dual-target inhibitors to highlight the potential of targeting heat shock proteins for cancer treatment. In summary, this review highlights how targeting heat shock proteins could regulate the hallmarks of cancer, which will provide valuable information to better elucidate and understand the roles of heat shock proteins in oncology and the mechanisms of cancer occurrence and development and aid in the development of more efficacious and less toxic novel anticancer agents.

Immunogenic cell death (ICD) is a stress-driven form of regulated cell death (RCD) in which dying tumor cells' specific signaling pathways are activated to release damage-associated molecular patterns (DAMPs), leading to the robust anti-tumor immune response as well as a reversal of the tumor immune microenvironment from "cold" to "hot". Chimeric antigen receptor (CAR)-T cell therapy, as a landmark in anti-tumor immunotherapy, plays a formidable role in hematologic malignancies but falls short in solid tumors. The Gordian knot of CAR-T cells for solid tumors includes but is not limited to, tumor antigen heterogeneity or absence, physical and immune barriers of tumors. The combination of ICD induction therapy and CAR-T cell immunotherapy is expected to promote the intensive use of CAR-T cell in solid tumors. In this review, we summarize the characteristics of ICD, stress-responsive mechanism, and the synergistic effect of various ICD-based therapies with CAR-T cells to effectively improve anti-tumor capacity.

The activating transcription factor (ATF)/ cAMP-response element binding protein (CREB) family represents a large group of basic zone leucine zip (bZIP) transcription factors (TFs) with a variety of physiological functions, such as endoplasmic reticulum (ER) stress, amino acid stress, heat stress, oxidative stress, integrated stress response (ISR) and thus inducing cell survival or apoptosis. Interestingly, ATF family has been increasingly implicated in autophagy and ferroptosis in recent years. Thus, the ATF family is important for homeostasis and its dysregulation may promote disease progression including cancer. Current therapeutic approaches to modulate the ATF family include direct modulators, upstream modulators, post-translational modifications (PTMs) modulators. This review summarizes the structural domain and the PTMs feature of the ATF/CREB family and comprehensively explores the molecular regulatory mechanisms. On this basis, their pathways affecting proliferation, metastasis, and drug resistance in various types of cancer cells are sorted out and discussed. We then systematically summarize the status of the therapeutic applications of existing ATF family modulators and finally look forward to the future prospect of clinical applications in the treatment of tumors by modulating the ATF family.

Prostate cancer (PCA) is one of the most prevalent types of male cancers. While current treatments for early-stage PCA are available, their efficacy is limited in advanced PCA, mainly due to drug resistance or low efficacy. In this context, novel valuable therapeutic opportunities may arise from the combined inhibition of histone deacetylase 6 (HDAC6) and heat shock protein 90 (Hsp90). These targets are mutually involved in the regulation of several processes in cancer cells, and their inhibition is demonstrated to provide synergistic effects against PCA. On these premises, we performed an extensive in silico virtual screening campaign on commercial compounds in search of dual inhibitors of HDAC6 and Hsp90. In vitro tests against recombinant enzymes and PCA cells with different levels of aggressiveness allowed the identification of a subset of compounds with inhibitory activity against HDAC6 and antiproliferative effects towards LNCaP and PC-3 cells. None of the candidates showed appreciable Hsp90 inhibition. However, the discovered compounds have low molecular weight and a chemical structure similar to that of potent Hsp90 blockers. This provides an opportunity for structural and medicinal chemistry optimization in order to obtain HDAC6/Hsp90 dual modulators with antiproliferative effects against prostate cancer. These findings were discussed in detail in the study.

Alpha-fetoprotein (AFP) elevation is a well-known biomarker in various diseases, particularly in the diagnosis of hepatocellular carcinoma (HCC). Intracellular AFP has been previously implicated in promoting tumorigenesis. In this study, we discovered that AFP enhances the stability of oncoproteins c-MYC and c-MET, thereby facilitating the progression of liver and gastric tumors. Our findings suggest that AFP acts by stabilizing these oncoproteins, which are clients of heat shock protein 90 (HSP90), and prevents their degradation through ubiquitination. Intriguingly, we identified AFP as a novel co-chaperone of HSP90, demonstrating its ability to regulate the stabilization of HSP90 client proteins. Furthermore, our results indicate that inhibiting AFP or HSP90 enhances the cytotoxicity of chemotherapeutic agents in AFP-producing HCC and gastric cancer cells. These findings have significant implications for the development of therapeutic strategies targeting AFP-producing tumors, as the AFP-HSP90-mediated activation of c-MYC and c-MET provides new insights into potential treatment approaches. In summary, this study sheds light on the role of AFP in promoting tumor progression by stabilizing oncoproteins through its interaction with HSP90. The identification of this mechanism opens up new avenues for therapeutic interventions in AFP-producing tumors.

Triple-negative breast cancer (TNBC) remains a treatment challenge and requires innovative therapies. Hsp90, crucial for the stability of numerous oncogenic proteins, has emerged as a promising therapeutic target. In this study, we present the optimization of the Hsp90 C-terminal domain (CTD) inhibitor TVS21. Biochemical methods, NMR binding studies, and molecular modeling were employed to investigate the binding of representative analogs to Hsp90. The newly synthesized analogs showed increased antiproliferative activity in breast cancer cell lines, including the MDA-MB-231 TNBC cell line. Compounds 89 and 104 proved to be the most effective, inducing apoptosis, slowing proliferation, and degrading key oncogenic proteins without inducing a heat shock response. In vivo, compound 89 showed comparable efficacy to the clinical candidate AUY922 and a better safety profile in a TNBC xenograft model. These results highlight the promise of Hsp90 CTD inhibitors for TNBC therapy, potentially filling a significant treatment gap.