Due to its low cost-effectiveness and insulating qualities, asbestos has been widely used since the middle of the 20th century. Since the last decade of the 20th century, asbestos use has been strictly regulated in the United States and banned in Europe and Australia due to in vivo evidence of its carcinogenic potential [9]. The word “asbestos” is used in national regulatory papers to refer to six commercially exploited minerals: one serpentine (chrysotile) and five amphiboles (crocidolite, actinolite, tremolite, anthophyllite, and amosite). On the other hand, about 400 other minerals with comparable chemical and physical characteristics are found in the natural environment; their usage is uncontrolled, and they are not subject to regulations. Moreover, naturally occurring erionite fibers, which are even more carcinogenic than asbestos, have been utilized for building and road paving materials, and residents of some Cappadocian villages in Turkey and in some areas of North Dakota (US) are exposed to these fibers [10,11]. It is now commonly known that specific mineral fiber types have different carcinogenic potencies depending on their size, durability, dose, and physical characteristics [12,13,14]. Thin, long fibers have been linked to increased mutagenic and cytotoxic efficacy [15] due to the release of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in response to “frustrated phagocytosis” [16,17,18]. However, due to its significantly lower inflammatory response when compared to carcinogenic fibers, palygorskite—a fiber that is highly prevalent in southern Nevada—was unable to promote cancer in vivo while having lower in vitro cytotoxicity and biopersistence [19]. The mechanisms underlying asbestos carcinogenesis have long been enigmatic [20,21]. However, mesothelial cells undergo an equivalent transformation under extended contact to chrysotile fibers [17,18]. Furthermore, it has been demonstrated that ROS released by asbestos-activated macrophages may indirectly cause DNA damage by forming 8-hydroxy-2′-deoxyguanosine (8-OHdG) adducts [22]. According to recent research on iron-catalyzed ROS production, asbestos-related carcinogenesis may entail ferroptosis, a non-apoptotic, iron-dependent cell death mechanism [23]. Furthermore, through stimulation of the PI3K/MEK5/Fra-1 axis, hepatocyte growth factor (HGF) has been implicated in asbestos-induced carcinogenesis [24]. However, human mesothelial cells (HM), a kind of cell that is especially vulnerable to fiber cytotoxicity and was previously thought to be apoptotic, die when exposed to asbestos particles [25]. Later, it was evident that tumor necrosis factor-alpha (TNF-α), an inflammatory mediator, was linked to the pathogenesis of asbestos [26]. One of the main contributing factors to the pathophysiology and carcinogenesis caused by asbestos and other mineral fibers known to cause cancer is chronic inflammation. The pro-inflammatory milieu created at the fiber deposition site by macrophages and PM, along with the biopersistence of many mineral fibers, enables the avoidance of cell death and ultimately leads to neoplastic transformation [27,28]. The passive release of high mobility group box 1 (HMGB1) by necrotic PM at the location of fiber deposition characterizes this controlled form of necrosis. One such damage-associated molecular protein (DAMP) is HMGB1, which encourages the macrophage recruitment necessary to maintain the chronic inflammatory process. To prime macrophages for inflammasome activation, HMGB1 binds to RAGE and other HMGB1 receptors. This, in conjunction with other stimuli, such as endogenous ROS produced following asbestos exposure, causes the NLRP3 inflammasome to assemble through the oligomerization of inactive NLRP3, apoptosis-associated speck-like protein (ASC), and procaspase-1. IL-1β, IL-18, IL-1α, and HMGB1 are released when the NLRP3 inflammasome is activated, initiating an autocrine chronic inflammatory process [29,30]. Additionally, TNF-α is secreted during this process, which stimulates NF-κB and increases HM’s chance of survival after asbestos exposure. Mesothelioma occurs because of the surviving HM’s continued proliferation and accumulation of genetic alterations. Furthermore, it was observed that ethyl pyruvate, which has been identified as an efficient HMGB1 inhibitor and suppressor of RAGE receptor expression, decreased the proliferation of mesothelioma cells both in vitro and in vivo. Both actions help to lower the malignancy of mesothelioma [31]. Whereas HMGB1 is primarily identified in the nucleus of HM, it has also been detected in the cytoplasm and nucleus of mesothelioma. HMGB1 is actively secreted into the extracellular space during mesothelioma, where it binds to RAGE and TLR receptors to form an autocrine pathway that stimulates the growth, motility, and survival of the cancerous cells [32].

As not all PM patients have a history of asbestos exposure, asbestos fibers primarily cause mortality by necrosis and, to a lesser extent, through other cell death processes. Somatic gene mutations that impact DNA repair processes are frequently linked to carcinogenesis, as they cause an increase in the fraction of cells with damaged DNA and the accumulation of damage to DNA. Cancer may arise when these cells develop survival mechanisms like to those triggered by the HMGB1 pathway in mesothelioma. Inherited mutations that impact DNA repair and other genes may exacerbate the carcinogenesis process by making an individual more vulnerable to environmental carcinogens [33,34]. The present method used to investigate GxE interactions in the realm of carcinogens combines genetics (G) and environmental (E) investigations. Recently, the increase in the level of mutations in the genome of cancer cells has been linked to the catastrophic event known as chromothripsis. A single, segregated chromosome that is randomly reassembled can break, resulting in chromothripsis, which causes erroneous rearrangements or deletions of DNA sequences. As a result, huge genomic changes could happen after just one chromothripsis event. This elevated mutational status ultimately promotes carcinogenesis by favoring oncogene activations or the loss of tumor suppressor activities [35]. Notably, noncontiguous biallelic genome alterations with the characteristic pattern of chromothripsis and associated with possible neoantigen expression were found in genomic studies of mesothelioma cells and specimens. These findings may have intriguing implications for the immunogenicity of mesothelioma [36,37,38]. Mutations were discovered in several tumor suppressors connected to apoptosis and cell cycle regulation in human mesothelioma. The homozygous deletion on locus 9p21, which impacts the transcription of two tumor suppressors—p16INK4a and p14ARF—is one of the main genetic abnormalities seen in mesothelioma [39]. By attaching to CDK4 and CDK6, P16INK4a prevents cell proliferation, and p14 encourages apoptosis by preventing p53 ubiquitylation. Up to 80% of primary pleural mesotheliomas lacked p16, according to cytogenetic research, and p16 inactivation is associated with a worse prognosis [40]. Transgenic p14 (+/−) mice showed decreased heterogeneity for p14 in their extracted primary mouse tumors, and these mice were more prone to asbestos-induced carcinogenesis [41]. Mesothelioma also exhibits significant mutations in Hippo signaling pathway intermediates. In almost 40% of cases of malignant mesothelioma, the upstream initiator of Hippo, neurofibromatosis type 2 (NF2)/Merlin, is inactive [42]. Remarkably, after BRCA1-related protein-1, NF2 is the second most often mutated gene in mesothelioma (BAP1). Compared to wildtype controls, heterozygous NF2 (+/−) mice showed an accelerated carcinogenesis and were more susceptible to asbestos exposure [43]. In the Hippo pathway, nonfunctional NF2 causes nuclear accumulation of WW Domain-contain transcription regulator (WWTR1 or TAZ) and yes-associated protein (YAP). One effect of the pro-inflammatory milieu created by asbestos fiber exposure is the increased nucleus formation of the YAP/TAZ complex, which, in turn, stimulates the expression of several proto-oncogenes and supports the survival of cancer cells [44]. It was feasible to identify potential frequent abnormalities at chromosome 3p21 in two unrelated US families with a high incidence of mesothelioma and no occupational asbestos exposure as a result of linkage analysis and array-comparative genomic hybridization (aCGH). Following sequencing, germline BAP1 mutations linked to autosomal dominant transmission of uveal melanoma and mesothelioma were discovered [45,46]. The BAP1-related cancer syndrome was discovered in individuals with germline altered BAP1 prone to additional cancer forms such renal cell carcinoma and squamous cell carcinoma [45,47,48]. According to recent research, BAP1 has multiple activities in the cytoplasm and nucleus that work together to prevent tumor growth. The endoplasmic reticulum (ER) fraction is the primary location of cytoplasmic BAP1, where it deubiquitylates and stabilizes the type 3 inositol-1,4,5-trisphosphate receptor (IP3R3). Via the mitochondrial uniporter channel (MUC) in the inner mitochondrial membrane and the voltage-dependent anion channels (VDACs) in the outer mitochondrial membrane, IP3R3 facilitates the release of Ca²⁺ from the ER into the mitochondrial space. The release of cytochrome c, which triggers apoptosis, is caused by an increase in Ca²⁺ concentration in the mitochondria. Reduced BAP1 dosage affects both DNA repair, accumulated DNA damage, and the apoptotic response in heterozygous BAP1+/− circumstances, such as in individuals in the families with the BAP1 cancer syndrome. This double function both favorably selects cells with cancer-causing mutations and encourages the growth of tumors [46]. The delineation of the intricate web of molecular processes mediated by asbestos carcinogenesis was aided by the discovery of BAP1 as a primary regulator of metabolism and cell death [48]. To fully understand the role of the genes predisposing to mesothelioma in the molecular pathways of asbestos carcinogenesis, more research will be necessary.