The sun produces electromagnetic radiation that encompasses a broad range of wavelengths. Among them, only a few wavelengths are able to pass through the ozone layer and reach the earth surface; these include ultraviolet (UV) radiation, infrared (IR), and visible light (VL). Solar UV radiations occur in the wavelength range of around 200–400 nm; however, only UVA (400–315 nm) and UVB (315–280 nm) can reach the earthbound surface, while UVC (280–100 nm) is completely absorbed by the ozone layer (Svobodová et al., 2003). Fig. 1 demonstrates how extreme exposure to UVB harms the capacity of basal keratinocytes for maintaining skin homeostasis and will prompt different skin diseases, which incorporate erythema, edema, sunburn, keratinocyte hyperplasia, and causes DNA mutations, photo-aging, and skin cancer (Strozyk and Kulms, 2013).

UVB radiation instigated Different DNA damage classes, specifically cyclobutane pyrimidine dimers (CPDs), pyrimidine (6-4) photoproducts (6-4PPs), DNA strand breaks, and DNA cross-links (Brash, 1997). CPDs are the most cytotoxic lesions which are responsible for cell death, but 6-4PPs cause more prominent alterations in the structure of the DNA double helix (Kciuk et al., 2020) and UVA does not induce 6-4PPs. However, longer UV wavelengths cause more DNA strand breaks (Sczepanski et al., 2009). Upon exposure to UVA or UVB, 6-4PPs undergo photoisomerization to Dewar isomers (Kciuk et al., 2020). Tandem pyrimidine residues form at the site of UV-induced DNA damage (Rochette et al., 2003). After DNA damage, cells respond by promptly halting cell division to prevent further DNA damage, which allows the DNA repair mechanism to begin. If the DNA damage induced by UVB is not fixed, it brings about mutations in the genome, prompting skin carcinogenesis (Brash et al., 1991). NER is essential in the repair of CPDs and 6-4 PPs (Sugasawa et al., 1998). The p53 mutations, which include T → C transition or double base changes such as TT → CC transition, are frequently found in all types of skin malignancies, the so-called “UVB signature” (Wikonkal and Brash, 1999). UVA radiation causes indirect DNA damage by driving photons and energy transfer from cellular photosensitizers, such as porphyrins, bilirubin, and melanin, to oxygen molecules leading to the formation of singlet oxygen, which induces guanine moiety oxidation followed by structural rearrangement and formation of 8-oxo-7,8-dihydroguanine (8-oxo-G) and 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxo-dG) (Klungland et al., 1999).

The chief cause of both BCC and SCC is exposure to UVR. Almost all BCC occur on UVR-exposed body sites, and SCC originates from a malignant mutation of keratinocytes in the epidermis and skin adnexa and is capable of metastasis (Lo and Fisher, 2014). Early diagnosis of both BCC and SCC can be treated, but the metastatic potential of BCC and SCC is really lethal (Kumar et al., 2015). Studies have proven that UV-induced DNA damage is the chief source of SCCs (Brash et al., 1991). Tumor growth was controlled by Ras proteins which incorporate H-ras, K-ras, and N-ras (Bos, 1989). Any changes in Ras oncogene leads to NMSCs (Pierceall et al., 1991). Hedgehog signaling, which is one of the very important pathways in embryonic development and furthermore identified to be associated with cancer promotion, was regulated by genomic phenylthiocarbamide protein (Wicking et al., 1997).

Vulnerability to ultraviolet radiation is the fundamental source of skin carcinogenesis that disrupts cutaneous cells by reactive oxygen species (ROS) overproduction (Liu-Smith et al., 2017). Direct exposure of the epidermis to UVR can lead to oxidative stress through NADPH oxidase activation or by prompting lipid peroxidation, which initiates ROS. Substantial increase in ROS by UVB irradiation triggers nuclear DNA damage via the development of cyclobutane pyrimidine dimers (CPDs), pyrimidine (6-4) photoproducts, and 8-hydroxy-2′-deoxyguanine (8-OHdG) (Gilbert et al., 2012). 8-OHdG, a biomarker for oxidative DNA damage, binds with adenine rather than cytosine, suggesting that oxidative damage can be tumorigenic (Agar et al., 2004). ROS-mediated carcinogenesis is of two types–genotoxic and non-genotoxic(Benedetti et al., 2021). ROS-mediated genotoxicity causes protooncogene actuation (BRAF, N-Ras, Ras-related C3 botulinum toxin substrate 1, phosphatase and tensin homolog etc.), tumor suppressor gene deactivation (p53 and protein patched homolog 1), genomic instability, and epigenetic modification. These alterations may further lead to mutations (Farhood et al., 2019; Xian et al., 2019). Fig. 2 represents the non-genotoxicity-intervened carcinogenesis that circuitously affects DNA via activation of various pathways-oxidative-stress related pathways and antioxidant stress pathways (Farhood et al., 2019; Xian et al., 2019).

ROS induced by UVB is produced through various mechanisms. The very first mechanism is the induction of ROS by the enzyme catalase. Through the catalytic activity, the enzyme catalase degrades hydrogen peroxide into water and oxygen (de Jager et al., 2017). The other antioxidant enzymes, such as glutathione and superoxide dismutase (SOD), are involved in scavenging ROS (Benedetti et al., 2021; Kora et al., 2023). Due to increased ROS production by UVB, these antioxidants fail to scavenge ROS, which altogether results in photocarcinogenesis (Xian et al., 2019). ROS production leads to the activation of mitogen-activated protein kinases (MAPKs), such as extracellular-signal-regulated kinase (ERK) and c-Jun N-terminal kinases (JNK), further leading to the downstream activation of transcription factor AP-1. The regulation of genes involved in the cell cycle, proliferation, and apoptosis is controlled by activator protein 1 and nuclear factor κB (NF-kB) (Bickers and Athar, 2006).

Overexposure to UVR, particularly UVB, can cause inflammation of the skin. Inflammation is the self-defensive response of the body and is classified into-(i) acute inflammation-caused as a result of exposure to any causative agents, which starts rapidly and becomes severe within a few; (ii) chronic inflammation, which can last for a few weeks to several months. Studies have shown that there is a strong relationship between UVR-spurred inflammation and cancer in the skin. Cancer mostly forms at the site of chronic inflammation (Balkwill and Mantovani, 2001). Exposure to UVB primes the secretion of various cytokines and chemokines from different skin cells, i.e., keratinocytes and Langerhans cells secretes a number of cytokines, such as transforming growth factor beta (TGFβ), tumor necrosis factor-alpha (TNFα), growth factors such as platelet-derived growth factor (PDGF), nerve growth factor (NGF), colony stimulating factor-1 (CSF-1), etc., and interleukins such as IL-1β, IL-6, IL-8, IL-10, and IL-12. UVB irradiation induces keratinocytes to deliver these cytokines, and the liberation of this production has been depicted in several skin cancers (van Kempen et al., 2003).

The activation of p38, MAPK, and Akt by UVB helps in the endurance of keratinocytes and opposes apoptosis that results in the accumulation of DNA damage, which may prompt malignant growth (Lee et al., 2011). UVB instigates the PI3K pathway for cell survival and aggravation, accomplished as a downstream movement of epithelial growth factor receptor (Wan et al., 2001). DNA damage by UVB is sufficient to intervene in NF-kB stimulation (Abeyama et al., 2000). Besides, (Simon et al., 1994) showed that UVB can directly actuate NF-kB from chromosomal DNA damage. Inhibitors of nuclear factor-kB kinase alpha (IKKα) and NF-kB assume a major function in maintaining skin homeostasis. Decrease in the outflow of IKKα promotes UVB-induced chronic inflammation and the process of carcinogenesis in mice models (van Kempen et al., 2003). IKKα similarly has a role in the promotion of SCC (Van Waes et al., 2007).

Solar UVB is a potent genotoxic agent that leads to apoptosis, portrayed by membrane blebbing and nuclear fragmentation (Su et al., 2015). Skin cells activate apoptosis to overcome the damage caused by UVB (Van Waes et al., 2007). UVB irradiation, a strong inducer of apoptosis in cultured cells, triggers both intrinsic and extrinsic pathways (Su et al., 2015). However, a few cells escape and may result in tumorigenesis. Henceforth, for the protection of normal cells from UVB, apoptosis aids as an essential process (Elmore, 2007; Zhang et al., 2023).

(i) Intrinsic pathway: UVB-triggered cell death generally occurs through the intrinsic apoptotic pathway, which is initiated by p53. Transformed p53 often exists in non-melanoma skin cancers (Rodust et al., 2009). In mitochondria, p53 increases the production of the pro-apoptotic protein, such as Bcl-2 associated X-protein (Bax), and diminishes the action of anti-apoptotic proteins, for example, B-cell lymphoma 2 (Bcl-2). The modification of the outer mitochondrial membrane structure by UVB gives rise to an imbalance in Bax/Bcl-2 ratio and delivers cytochrome c. Once delivered, cytochrome c and the apoptotic protease activating factor-1 form the apoptosome. This protein complex recruits and enacts caspase 9 and 3, bringing about apoptosis (Singh et al., 2019).

(ii) Extrinsic pathway: The multimerization of CD95 (Fas/APO-1) by UVB brings out its attachment to the adapter protein Fas-associated protein with death domain, followed by the activation of caspase cascade from caspase 8 to caspase 3 (Bang et al., 2003). After UVB irradiation, the TNF receptor is grouped and internalized in keratinocytes. TRAIL receptors, including TRAIL-R1 and TRAIL-R2, serve as lure receptors because of their competitive binding to cease apoptosis. UVB irradiation may change this equilibrium and may induce TRAIL-mediated apoptosis by the hindrance of binding with lure receptors (Qin et al., 2004).

In the property of invasiveness, EMT plays a leading role in which the phenotypic changes combined with EMT contribute to tumor heterogeneity and therapeutic resistance (Shu et al., 2013; Veloz et al., 2021). EMT is facilitated by EMT-inducing transcription factors (EMT-TFs) and is connected with normal organ advancement, wound healing, and the intrusiveness of cancer cells (Sato et al., 2016). TGF-β is the key regulator persuader of EMT; also, the epidermal growth factor (EGF), fibroblast growth factor, hepatocyte growth factor, Wnt, and ECM components have been proven to prompt this action (Nieto and Cano, 2012). EMT-TFs can be classified into two groups, in which one group suppresses the expression of E-cadherin, Snail, Slug, ZEB1, ZEB2, E47, KLF8, and Brachyury directly correlate with the E-cadherin gene promoter to arrest gene expression. In contrast, the other group-Twist1, FOXC2, Goosecoid, E2-2, SIX1, and PRRX1 trigger the EMT without direct attachment to the E-cadherin gene promoter (De Craene and Berx, 2013; Yang et al., 2021). N-cadherin, fibronectin, and vimentin are the mesenchyme-associated genes whose expression is initiated by EMT-TFs. EMT prompts the up-regulation of N-cadherin and simultaneous down-regulation of E-cadherin, termed as “Cadherin Switch Field” (Tyagi et al., 2015). In various human cancers, overexpression of EMT-TFs has been identified in various human cancers (De Craene and Berx, 2013). UVB-irradiated HaCaT cells exhibit amplified aggressiveness with exaggerated migration and invasive potential, and mesenchymal phenotypes, which validate that UVB causes EMT and is related to skin carcinogenesis (Tyagi et al., 2015).

Fatty acids (FA) are essential components for energy metabolism, stability of cell membranes, and modulation in multiple biological processes. Based on the hydrocarbon chain length, FA is classified into short-, medium- and long-chain fatty acids (Fung et al., 2011). The FA are mainly produced in the diet. SCFA can be easily absorbed, recycled, and metabolized in the body to make the body functional. Fig. 3 presents the pathway for SCFA production.

Even though the uptake of long-chain fatty acids (LCFA) and medium-chain fatty acids (MCFA) occur through similar mechanisms, there exist some differences. Both LCFA and MCFA are absorbed to some extent, and are the rate-limiting step for MCFA and LCFA is passaging across the brush-border membrane and unstirred water layer (UWL), respectively (Schönfeld and Wojtczak, 2016; Xu et al., 2021). For cellular uptake, intracellular transport, and metabolism, LCFA needs free fatty acid-binding proteins. However, SCFAs require no or much fewer free fatty acid binding proteins for their intracellular transport and metabolism. Also, SCFAs are secreted endogenously, whereas MCFAs and LCFAs are exogenous (Schönfeld and Wojtczak, 2016).

Based on the efficiency and bioavailability of SCFA, it is broadly used in research. Acetate (C2), propionate (C3), and butyrate (C4) are most abundantly secreted SCFAs via the gut flora as an end product of anaerobic fermentation (Fig. 3) (Parada Venegas et al., 2019). In the gut, Bacteroidetes and Firmicutes are the predominant bacterial phyla, whereas Actinobacteria, Proteobacteria, and Verrucomicrobia are the minor phyla. These microbes ferment most of the dietary substances and produce an array of metabolites, in which many are beneficial (Kobayashi et al., 2018). SCFAs have been linked to beneficial effects on human health associated with their metabolic and signaling properties. Fig. 4 represents the regulatory functions of SCFAs produced by gut flora will depend on specific receptors expressed in different cell types, which are mainly free fatty acid receptors (Keshari et al., 2019).

Each SCFAs bind to its specific free fatty acid receptors and mediates the cyclic adenosine monophosphate (cAMP) or extracellular-signal-regulated kinase 1/2 (ERK 1/2) signaling via G-protein dependent or independent pathways (Marinissen and Gutkind, 2001). The epithelial cells have free fatty acid receptors FFAR3 or GPR41, FFAR2 or GPR43, and GPR109A. Enteric neurons and intestinal leukocytes express GPR41 and GPR43, respectively, while intestine endocrine cells express both GPR41 and GPR43 (Sivaprakasam et al., 2016). The list of SCFAs receptors and their functions are briefed in Table 1.

The comprehensive anti-tumor properties of acetate, propionate, and butyrate are mentioned in this review. Butyrate renders protection against carcinogenesis by delivering 70% energy to colonocytes and sustains intestinal barrier functions, reducing inflammation (Bedford and Gong, 2018). Butyrate is produced by specific gut bacteria that come under the order Clostridiales, such as Lachnospiraceae (Coprococcus, Eubacterium, Anaerostipes, and Roseburia), Ruminococcaceae (Faecalibacterium and Subdoligranulum) and Erysipelotrichaceae (Holdemanella) (Louis et al., 2014; Flint, 2016). Many investigations have shown that butyrate exhibits anti-cancer activity through various signaling pathways that control cell survival and apoptosis in multiple cancer cells (Candido et al., 1978). Detailed information on the effects of butyrate on oncogenic signaling pathways is provided in an earlier publication (Chen et al., 2019). In vivo investigations revealed that butyrate diminishes the rate of colon cancer (McIntyre et al., 1993). Gonçalves et al. (2011) indicated that butyrate is a breast cancer-resistant protein (BCRP) substrate. Butyrate-induced apoptosis in a colon cancer cell line HCT116 (Fung et al., 2011). The anti-cancer effect of butyrate was explored in a breast cancer cell line MCF-7 (Yonezawa et al., 2007). The viability of U937 leukemia cells was decreased by butyrate to about 60% (Pulliam et al., 2016). 12-0-tetradecanoylphorbol-13-acetate (TPA) induced skin tumors in mice were reduced by topical application of butyric acid (Gupta and Mehrotra, 1997). This provides us the evidence that butyrate has anti-cancer properties against multiple cancer cell types.

Acetate is one of the most important SCFAs and has been less explored than propionate and butyrate. Also, acetate is the net fermentation end product for most gut bacteria, while butyrate and propionate are produced by very specific species (Martin-Gallausiaux et al., 2021). Acetate impedes proliferation and stimulates apoptosis in colon cancer cells, also acetate-induced apoptosis in CRC cells, further roots to mitochondrial alterations (Marques et al., 2013). The primary end products of Propionibacteria were acetate and propionate, which destroys two human adenocarcinoma cell lines by apoptosis through co-cultures with the dairy species Propionibacterium freudenreichii and Propionibacterium acidipropionici (Jan et al., 2002).

The anti-inflammatory properties of acetate and propionate were proved in human monocytes and in vivo colitis models (Cox et al., 2009; Maslowski et al., 2009). Propionate is considered the most powerful endogenic agonist for both G-protein coupled receptors, free fatty acid receptor 3 (FFA3) and FFA2 (Brown et al., 2003; Le Poul et al., 2003). Propionate is produced by Bacteroidetes and some Firmicutes, such as the Negativicutes (Veillonella and Phascolarctobacterium). Some other Firmicutes, belonging to Negativicutes (Megasphaera), Lachnospiraceae (Coprococcus), Ruminococcaceae, Proteobacteria, and Lachnospiraceae species (Martin-Gallausiaux et al., 2021). In vitro studies have shown that propionate reduces BaF3 cell proliferation through a cAMP level-dependent pathway, and FFA2 activation changes BaF3 cell growth which shows that propionate decreases cancer cell proliferation in the liver. An ongoing investigation (Høgh et al., 2020) revealed that the propionate causes metabolic changes bringing about the natural-killer group 2, member D (NKG2D) ligand surface expression, which renders as a potential immune activating anti-cancer therapy. Also, studies by Kim et al. (2019) have demonstrated that propionate prompts cell apoptosis and cell cycle arrest in lung cancer.

The anti-cancer properties of these SCFAs against colorectal cancer cells has been listed in numerous publications (Gu et al., 2012; Kobayashi et al., 2018; Ohara and Suzutani, 2018; You et al., 2018). In human colon cells and neutrophils, the anti-proliferative capacity of SCFAs has been related to the capacity of SCFA to hinder histone deacetylase function (Aoyama et al., 2010). The most remarkable histone deacetylase inhibitor is butyrate, though propionate exhibited the intermediate profile and acetate didn’t impact the deacetylase activity (Aoyama et al., 2010). Studies by (Maslowski et al., 2009; Pirozzi et al., 2018; Keshari et al., 2019) have shown that butyric acid from skin commensal bacteria reduces inflammation by binding to its free fatty acid receptors. Fig. 5 shows the possible molecular mechanisms of small-chain fatty acids in cancer cell inhibition (He et al., 2020).