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To investigate whether novel pathways of vitamin D3 (D3) and 7-dehydrocholesterol (7DHC) metabolism initiated by CYP11A1 and previously characterized in vitro , occur in vivo , we analyzed samples of human serum and epidermis and pig adrenals for the presence of intermediates and products of these pathways. We extracted human epidermis from 13 individuals and sera from 13 individuals and analyzed them by LC/qTOF-MS alongside the corresponding standards. Pig adrenal glands were also analyzed for these steroids and secosteroids. Epidermal, serum and adrenal samples showed the presence of D3 hydroxy-derivatives corresponding to 20(OH)D3, 22(OH)D3, 25(OH)D3, 1,25(OH) 2 D3, 20,22(OH) 2 D3, 20,23(OH) 2 D3, 20,24(OH) 2 D3, 20,25(OH) 2 D3, 20,26(OH) 2 D3, 1,20,23(OH) 3 D3 and 17,20,23(OH) 3 D3, plus 1,20(OH) 2 D3 which was detectable only in the epidermis. Serum concentrations of 20(OH)D3 and 22(OH)D3 were only 30- and 15-fold lower than 25(OH)D3, respectively and at levels above those required for biological activity as measured in vitro . We also detected 1,20,24(OH) 3 D3, 1,20,25(OH) 3 D3 and 1,20,26(OH) 3 D3 in the adrenals. Products of CYP11A1 action on 7DHC, namely 22(OH)7DHC, 20,22(OH) 2 7DHC and 7-dehydropregnenolone were also detected in serum, epidermis and the adrenal. Thus, we have detected novel CYP11A1-derived secosteroids in the skin, serum and adrenal gland and based on their concentrations and biological activity suggest that they act as hormones in vivo .

Molecular fossils (or biomarkers) are key to unraveling the deep history of eukaryotes, especially in the absence of traditional fossils. In this regard, the sterane 24-isopropylcholestane has been proposed as a molecular fossil for sponges, and could represent the oldest evidence for animal life. The sterane is found in rocks ∼650–540 million y old, and its sterol precursor (24-isopropylcholesterol, or 24-ipc) is synthesized today by certain sea sponges. However, 24-ipc is also produced in trace amounts by distantly related pelagophyte algae, whereas only a few close relatives of sponges have been assayed for sterols. In this study, we analyzed the sterol and gene repertoires of four taxa (Salpingoeca rosetta, Capsaspora owczarzaki, Sphaeroforma arctica, and Creolimax fragrantissima), which collectively represent the major living animal outgroups. We discovered that all four taxa lack C30 sterols, including 24-ipc. By building phylogenetic trees for key enzymes in 24-ipc biosynthesis, we identified a candidate gene (carbon-24/28 sterol methyltransferase, or SMT) responsible for 24-ipc production. Our results suggest that pelagophytes and sponges independently evolved C30 sterol biosynthesis through clade-specific SMT duplications. Using a molecular clock approach, we demonstrate that the relevant sponge SMT duplication event overlapped with the appearance of 24-isopropylcholestanes in the Neoproterozoic, but that the algal SMT duplication event occurred later in the Phanerozoic. Subsequently, pelagophyte algae and their relatives are an unlikely alternative to sponges as a source of Neoproterozoic 24-isopropylcholestanes, consistent with growing evidence that sponges evolved long before the Cambrian explosion ∼542 million y ago.

Cellular lipids are speculated to act as key intermediates in Hedgehog signal transduction, but their precise identity and function remain enigmatic. In an effort to identify such lipids, we pursued a Hedgehog pathway inhibitory activity that is particularly abundant in flagellar lipids of Chlamydomonas reinhardtii, resulting in the purification and identification of ergosterol endoperoxide, a B-ring oxysterol. A mammalian analog of ergosterol, 7-dehydrocholesterol (7-DHC), accumulates in Smith–Lemli–Opitz syndrome, a human genetic disease that phenocopies deficient Hedgehog signaling and is caused by genetic loss of 7-DHC reductase. We found that depleting endogenous 7-DHC with methyl-β-cyclodextrin treatment enhances Hedgehog activation by a pathway agonist. Conversely, exogenous addition of 3β,5α-dihydroxycholest-7-en-6-one, a naturally occurring B-ring oxysterol derived from 7-DHC that also accumulates in Smith–Lemli–Opitz syndrome, blocked Hedgehog signaling by inhibiting activation of the essential transduction component Smoothened, through a mechanism distinct from Smoothened modulation by other lipids.

Ferroptosis, a form of regulated cell death that is driven by iron-dependent phospholipid peroxidation, has been implicated in multiple diseases, including cancer 1 , 2 – 3 , degenerative disorders 4 and organ ischaemia–reperfusion injury (IRI) 5 , 6 . Here, using genome-wide CRISPR–Cas9 screening, we identified that the enzymes involved in distal cholesterol biosynthesis have pivotal yet opposing roles in regulating ferroptosis through dictating the level of 7-dehydrocholesterol (7-DHC)—an intermediate metabolite of distal cholesterol biosynthesis that is synthesized by sterol C5-desaturase (SC5D) and metabolized by 7-DHC reductase (DHCR7) for cholesterol synthesis. We found that the pathway components, including MSMO1 , CYP51A1 , EBP and SC5D , function as potential suppressors of ferroptosis, whereas DHCR7 functions as a pro-ferroptotic gene. Mechanistically, 7-DHC dictates ferroptosis surveillance by using the conjugated diene to exert its anti-phospholipid autoxidation function and shields plasma and mitochondria membranes from phospholipid autoxidation. Importantly, blocking the biosynthesis of endogenous 7-DHC by pharmacological targeting of EBP induces ferroptosis and inhibits tumour growth, whereas increasing the 7-DHC level by inhibiting DHCR7 effectively promotes cancer metastasis and attenuates the progression of kidney IRI, supporting a critical function of this axis in vivo. In conclusion, our data reveal a role of 7-DHC as a natural anti-ferroptotic metabolite and suggest that pharmacological manipulation of 7-DHC levels is a promising therapeutic strategy for cancer and IRI. 7-Dehydrocholesterol (7-DHC) is a natural anti-ferroptotic metabolite and pharmacological manipulation of 7-DHC levels shows promise as a therapeutic strategy for cancer and ischaemia–reperfusion injury.

Ferroptosis is a form of cell death that has received considerable attention not only as a means to eradicate defined tumour entities but also because it provides unforeseen insights into the metabolic adaptation that tumours exploit to counteract phospholipid oxidation 1 , 2 . Here, we identify proferroptotic activity of 7-dehydrocholesterol reductase (DHCR7) and an unexpected prosurvival function of its substrate, 7-dehydrocholesterol (7-DHC). Although previous studies suggested that high concentrations of 7-DHC are cytotoxic to developing neurons by favouring lipid peroxidation 3 , we now show that 7-DHC accumulation confers a robust prosurvival function in cancer cells. Because of its far superior reactivity towards peroxyl radicals, 7-DHC effectively shields (phospho)lipids from autoxidation and subsequent fragmentation. We provide validation in neuroblastoma and Burkitt’s lymphoma xenografts where we demonstrate that the accumulation of 7-DHC is capable of inducing a shift towards a ferroptosis-resistant state in these tumours ultimately resulting in a more aggressive phenotype. Conclusively, our findings provide compelling evidence of a yet-unrecognized antiferroptotic activity of 7-DHC as a cell-intrinsic mechanism that could be exploited by cancer cells to escape ferroptosis. Proferroptotic activity of 7-dehydrocholesterol reductase is shown along with an unexpected prosurvival function of its substrate, 7-dehydrocholesterol, indicating a cell-intrinsic mechanism that could be used by cancer cells to protect phospholipids from oxidative damage and escape ferroptosis.

Background Ferroptosis is an emerging cell death mechanism characterized by uncontrolled lipid peroxidation. However, selectively inducing ferroptosis in cancer cells remains a challenge. Methods We explore an approach that enables ferroptosis induction through external radiation. The key component of this technology is 7-dehydrocholesterol (7DHC), a natural biosynthetic precursor of cholesterol. To facilitate delivery, we demonstrate that 7DHC, like cholesterol, can be incorporated into the lipid layer of liposomes. To enhance targeting, we also introduced NTS mut , a ligand for the neurotensin receptor 1 (NTSR1), which is overexpressed in multiple malignancies, into liposomes. Results Under radiation, 7DHC reacts with radiation-induced reactive oxygen species (ROS), initiating a radical chain reaction with polyunsaturated fatty acids (PUFAs) in cell membranes. This process results in direct lipid peroxidation and subsequent ferroptotic cell death. In vivo studies demonstrate that NTS mut -conjugated, 7DHC-loaded liposomes (N-7DHC-lipos) effectively accumulate in tumors and significantly enhance the efficacy of radiation therapy. Conclusion While conventional radiosensitizers primarily target DNA and its repair mechanisms, our study introduces a strategy to enhance radiotherapy by specifically activating ferroptosis within the irradiated area, thereby minimizing systemic toxicity. Such a strategy of controlled activation of ferroptosis offers a favorable therapeutic index and potentially opens avenues for clinical application. Graphical Abstract

Smith-Lemli-Opitz syndrome (SLOS) is a multiple malformation/cognitive impairment syndrome characterized by the accumulation of 7-dehydrocholesterol, a precursor sterol of cholesterol. Simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor that crosses the blood–brain barrier, has been proposed for the treatment of SLOS based on in vitro and in vivo studies suggesting that simvastatin increases the expression of hypomorphic DHCR7 alleles. Safety and efficacy of simvastatin therapy in 23 patients with mild to typical SLOS were evaluated in a randomized, double-blind, placebo-controlled trial. The crossover trial consisted of two 12-month treatment phases separated by a 2-month washout period. No safety issues were identified in this study. Plasma dehydrocholesterol concentrations decreased significantly: 8.9 ± 8.4% on placebo to 6.1 ± 5.5% on simvastatin (P < 0.005); we observed a trend toward decreased cerebrospinal fluid dehydrocholesterol concentrations. A significant improvement (P = 0.017, paired t-test) was observed on the irritability subscale of the Aberrant Behavior Checklist–C when subjects were taking simvastatin. This article reports what is, to our knowledge, the first randomized, placebo-controlled trial designed to test the safety and efficacy of simvastatin therapy in SLOS. Simvastatin seems to be relatively safe in patients with SLOS, improves the serum dehydrocholesterol–to–total sterol ratio, and significantly improves irritability symptoms in patients with mild to classic SLOS. Genet Med19 3, 297–305.

The aim of this research was to design and synthesize new lipid conjugates of 7-DHC that could serve as a new storage form of esterified provitamin D , increasing the reservoir of this biomolecule in the epidermis and enabling controlled production of vitamin D even during periods of sunlight deficiency. Acylglycerol and glycerophospholipid containing succinate-linked provitamin D at the -2 position of the glycerol backbone were synthesized from dihydroxyacetone (DHA) and -glycerophosphocholine (GPC), respectively. The three-step synthesis of 1,3-dipalmitoyl-2-(7-dehydrocholesterylsuccinoyl)glycerol involved the esterification of DHA with palmitic acid, reduction of the carbonyl group, and conjugation of the resulting 1,3-dipalmitoylglycerol with 7-dehydrocholesterol hemisuccinate (7-DHC HS). The use of NaBH CN as a reducing agent was crucial to avoid acyl migration and achieve the final product with 100% regioisomeric purity. For the preparation of 1-palmitoyl-2-(7-dehydrocholesterylsuccinoyl)- -glycero-3-phosphocholine, a two-step process was applied, involving the esterification of GPC at the -1 position with palmitic acid, followed by the conjugation of 1-palmitoyl- -glycero-3-phosphocholine with 7-DHC HS. Alongside the main product, a small amount of its regioisomer with provitamin D linked at the -1 position and palmitic acid at the -2 position was detected, indicating acyl migration from the -1 to the -2 position in the intermediate 1-palmitoyl -glycerophosphocholine. The synthesized novel lipids were fully characterized using spectroscopic methods. They can find applications as novel lipid-based prodrugs as additives to sunscreen creams.

Liver X receptor (LXR) agonism has theoretical potential for treating NAFLD/NASH, but synthetic agonists induce hyperlipidemia in preclinical models. Desmosterol, which is converted by Δ24‐dehydrocholesterol reductase (DHCR24) into cholesterol, is a potent endogenous LXR agonist with anti‐inflammatory properties. We aimed to investigate the effects of DHCR24 inhibition on NAFLD/NASH development. Here, by using APOE*3‐Leiden. CETP mice, a well‐established translational model that develops diet‐induced human‐like NAFLD/NASH characteristics, we report that SH42, a published DHCR24 inhibitor, markedly increases desmosterol levels in liver and plasma, reduces hepatic lipid content and the steatosis score, and decreases plasma fatty acid and cholesteryl ester concentrations. Flow cytometry showed that SH42 decreases liver inflammation by preventing Kupffer cell activation and monocyte infiltration. LXRα deficiency completely abolishes these beneficial effects of SH42. Together, the inhibition of DHCR24 by SH42 prevents diet‐induced hepatic steatosis and inflammation in a strictly LXRα‐dependent manner without causing hyperlipidemia. Finally, we also showed that SH42 treatment decreased liver collagen content and plasma alanine transaminase levels in an established NAFLD model. In conclusion, we anticipate that pharmacological DHCR24 inhibition may represent a novel therapeutic strategy for treatment of NAFLD/NASH. Synopsis Non‐alcoholic fatty liver disease (NAFLD) affects over 30% of the general population, yet there is currently no medication available for its treatment. This study reports a novel strategy to activate liver X receptors (LXR) via pharmacological Δ24‐dehydrocholesterol reductase (DHCR24) inhibition for the treatment of NAFLD and potentially other cardiometabolic diseases. SH42 inhibits DHCR24 to increase levels of the endogenous LXR agonist desmosterol in the circulation and liver. Inhibition of DHCR24 exerts metabolic and immune benefits in a strictly LXRα‐dependent manner without causing hyperlipidemia. Inhibition of DHCR24 decreases liver collagen content and plasma alanine transaminase levels in an established NAFLD model. Graphical Abstract Non‐alcoholic fatty liver disease (NAFLD) affects over 30% of the general population, yet there is currently no medication available for its treatment. This study reports a novel strategy to activate liver X receptors (LXR) via pharmacological Δ24‐dehydrocholesterol reductase (DHCR24) inhibition for the treatment of NAFLD and potentially other cardiometabolic diseases.

Cytochrome P450scc metabolizes vitamin D3 to 20-hydroxyvitamin D3 (20(OH)D3) and 20,23(OH)(2)D3, as well as 1-hydroxyvitamin D3 to 1alpha,20-dihydroxyvitamin D3 (1,20(OH)(2)D3). It also cleaves the side chain of 7-dehydrocholesterol producing 7-dehydropregnenolone (7DHP), which can be transformed to 20(OH)7DHP. UVB induces transformation of the steroidal 5,7-dienes to pregnacalciferol (pD) and a lumisterol-like compounds (pL). To define the biological significance of these P450scc-initiated pathways, we tested the effects of their 5,7-diene precursors and secosteroidal products on leukemia cell differentiation and proliferation in comparison to 1alpha,25-dihydroxyvitamin D3 (1,25(OH)(2)D3). These secosteroids inhibited proliferation and induced erythroid differentiation of K562 human chronic myeloid and MEL mouse leukemia cells with 20(OH)D3 and 20,23(OH)(2)D3 being either equipotent or slightly less potent than 1,25(OH)(2)D3, while 1,20(OH)(2)D3, pD and pL compounds were slightly or moderately less potent. The compounds also inhibited proliferation and induced monocytic differentiation of HL-60 promyelocytic and U937 promonocytic human leukemia cells. Among them 1,25(OH)(2)D3 was the most potent, 20(OH)D3, 20,23(OH)(2)D3 and 1,20(OH)(2)D3 were less active, and pD and pL compounds were the least potent. Since it had been previously proven that secosteroids without the side chain (pD) have no effect on systemic calcium levels we performed additional testing in rats and found that 20(OH)D3 had no calcemic activity at concentration as high as 1 microg/kg, whereas, 1,20(OH)(2)D3 was slightly to moderately calcemic and 1,25(OH)(2)D3 had strong calcemic activity. We identified novel secosteroids that are excellent candidates for anti-leukemia therapy with 20(OH)D3 deserving special attention because of its relatively high potency and lack of calcemic activity.