Hepatocellular carcinoma (HCC) accounts for approximately 90% of primary liver cancer cases and is one of the most common cancers worldwide with dismal prognosis [1], with nearly 906000 new cases and 830000 deaths per year [2]. HCC has extremely high tumor heterogeneity and is highly insensitive to conventional radiotherapy and chemotherapy. For those patients with advanced HCC, the overall survival (OS) is of only 3-6 months, due to high intratumor heterogeneity and the lack of effective therapy[3]. At present, HCC diagnosis mainly relies on serum alpha fetoprotein (AFP) indicators and imaging examinations. Although some emerging detection techniques, such as liquid biopsies, are becoming increasingly mature, they have not yet entered clinical application [4], [5]. For patients with early-stage HCC, liver transplantation and surgical resection are the preferred treatment options. Unfortunately, approximately 80% of HCC cases are diagnosed at an advanced stage due to the lack of specific symptoms, and thus, only about 20-30% of patients can undergo radical surgery [6], [7]. Ablation therapy is effective for patients with single tumors who cannot tolerate surgery, but its efficacy could be significantly limited by tumor size and location [8], [9]. Patients with multiple lesions without extrahepatic metastases can benefit from transarterial chemoembolization (TACE) therapy, but TACE can in turn stimulate tumor angiogenesis, which is the main cause of tumor recurrence [10]. Systemic therapy has developed rapidly in recent years [11]. Among them, multikinase inhibitor sorafenib is a classic targeted agent for advanced HCC, but develops resistance after several years [12]. In recent years, the newly emerged multikinase inhibitor lenvatinib and the combination of atezolizumab (a PD-L1 antibody) and bevacizumab (an anti-vascular endothelial growth factor (VEGF) antibody) have become first-line therapies for advanced HCC, with objective response rates (ORRs) of 40.6% and 33.2%, respectively [13], [14]. Overall, although the level of diagnosis and treatment of HCC has been improving in the past few decades, the five-year survival rate is still only about 5-30% [15]. Therefore, it is of great clinical significance to elucidate the molecular mechanisms of HCC occurrence and progression and identify reliable biomarkers for more accurate diagnosis and treatment.

Heat shock proteins (HSP) are a highly conserved family of proteins that are ubiquitously expressed in cells. In normal human cells, HSPs stabilize multi-peptide complexes, assist newly synthesized proteins in correct folding, and prevent abnormal protein aggregation or degradation [16]. Cancer cells typically suffer from nutrient and energy deficiencies, hypoxia, or accumulation of metabolic products, which can lead to protein toxicity and high levels of oxidative stress, thereby destroying the stability of multiple proteases [17]. Thus, cancer cells or mutated cells can upregulate and activate HSPs to initiate protein stability maintenance mechanisms, thereby inhibiting apoptosis and promoting proliferation, metastasis and angiogenesis of tumors [18]. To date, numerous studies have demonstrated that HSPs also serve important roles in HCC. More importantly, many HSP inhibitors (such as PU-H71, NVP-AUY922, or SNX-2112) have shown promising therapeutic efficacy in patients with advanced HCC [19]. Here, we review current researches of HSPs in HCC, summarize the functions and possible mechanisms, and discuss potential clinical application of HSPs in HCC. We also provide a new insight of HSPs as diagnostic and prognostic biomarkers for HCC.