https://www.science.org/doi/10.1126/science.aec5473?referrer=https%3A%2F%2Fwww.linkedin.com%2F
(time to read ur garlic and other alliums book again)
Mechanistically, S8 reacted with abundant cellular thiols, such as glutathione (GSH), to generate antioxidant hydropersulfides and polysulfides that suppress lipid peroxidation.
[i wonder if it even interacts with modafinil]
The paper makes the pathway much more specific than I initially implied. The striking result is that NOS, particularly lipid-droplet-associated eNOS/NOS3, appears to be an S₈-producing enzyme. Mammalian S₈ reaches roughly millimolar concentrations in mitochondrial membranes and lipid droplets.
A useful working model is:
cysteine / sulfur metabolism → persulfides & polysulfides → NOS-associated sulfur chemistry → S₈ → lipid-droplet/mitochondrial S₈ reservoir → GSH + S₈ → hydropersulfides/polysulfides → antioxidant effects
The middle arrow is the exciting new territory. The paper establishes NOS-dependent S₈ production, but it does not yet give us a complete atom-by-atom metabolic flux map from dietary cysteine into S₈.
So what should actually increase S₈?
I’d separate candidates into four mechanistic buckets:
Input / manipulation Expected relevance to S₈ Why DATS / garlic polysulfides High plausibility Directly supplies transferable sulfane sulfur DADS Moderate-high Raises sulfane sulfur experimentally, but less reactive than DATS Cysteine / cystine Moderate Fundamental substrate feeding endogenous RSS synthesis H₂S donors Moderate-high mechanistic plausibility H₂S → SQR persulfide → GSSH/polysulfides GSSH / persulfides Very high mechanistic proximity Immediately adjacent sulfur pool NOS/eNOS activity Directly implicated New paper identifies NOS as an S₈ source GSH availability Complicated Can mobilize S₈ into GSSH rather than necessarily increase stored S₈ NAC Uncertain Raises cysteine/GSH, but could increase both production and consumption of S₈ Methionine Indirect Must travel through transsulfuration before reaching reactive sulfur chemistry Sulforaphane Probably mostly indirect Sulfur-containing electrophile/Nrf2 activator, not an obvious sulfane-S donor Modafinil Very low Sulfur stays embedded in sulfoxide/sulfone metabolites The endogenous sulfur network already contains several routes into persulfides. CBS/CSE can use cysteine, cystine and homocysteine; CARS can generate cysteine persulfide; mitochondrial SQR takes H₂S and produces protein-bound sulfur that can be transferred to GSH as GSSH.
That gives us an intriguing potential upstream route:
cysteine → CBS/CSE/CARS → H₂S/CysSSH
↓
mitochondrial SQR → GSSH / polysulfides
↓
sulfane-sulfur network
↓
NOS-dependent S₈ formationThe final connection is not yet established as a linear pathway, so I would not draw an enzymatic arrow from GSSH directly to eNOS/S₈ as fact.
Garlic suddenly looks unusually interesting
DATS is CH₂=CH−CH₂−S−S−S−CH₂−CH=CH₂.
The central sulfur behaves very differently from sulfur in an ordinary thioether or sulfoxide. Cellular thiols can attack DATS and transfer reactive sulfur into molecules such as allylpersulfide and GSSH. DATS can also directly transfer sulfane sulfur onto protein thiols.
And this isn’t purely test-tube chemistry. In mice:
DADS/DATS → ↑ total renal sulfane sulfur
and they also altered CSE/TST activity.
So I would revise my previous cartoon into:
DATS/DADS
→ sulfane-S / RSS pool
↔ CysSSH / GSSH / polysulfides
→ ??? NOS-dependent chemistry ???
→ S₈That
???is precisely where a very good follow-up paper lives.There is another possibility that is almost the mirror image:
DATS → RSS doesn’t necessarily make S₈.
It might instead reproduce some of S₈’s downstream chemistry, reducing the cell’s need to draw sulfur out of its S₈ reservoir. In that case DATS administration could paradoxically cause S₈ to accumulate, because consumption decreases.
Or it could increase S₈ synthesis by supplying excess reactive sulfur.
Those opposite predictions are why simply measuring S₈ after DATS would be unusually informative.
GSH is even more Janus-faced
The authors propose that stored S₈ can react with glutathione to generate antioxidant supersulfur species.
Therefore:
more GSH ≠ necessarily more S₈.
It could mean:
S₈ + GSH → GSSH / GSSₙH → less stored S₈
while cysteine/GSH also supports the upstream sulfur network that could eventually replenish S₈.
So NAC supplementation, for example, could theoretically increase S₈ synthesis or accelerate S₈ mobilization. Without isotope tracing, total S₈ concentration could actually conceal increased flux.
That’s an important distinction:
S₈ pool size ≠ S₈ synthesis rate.
A bathtub can have the same water level while both faucet and drain are roaring.
Why modafinil is almost certainly the wrong kind of sulfur
Modafinil’s sulfur is:
R−S(=O)−R
Its known metabolism is dominated by hydrolytic deamidation and further S-oxidation, giving modafinil acid and modafinil sulfone. Less than 10% is excreted unchanged.
Notice the direction:
modafinil sulfoxide → modafinil sulfone
That’s sulfur becoming more oxidized and remaining carbon-bound.
The interesting S₈/RSS chemistry instead involves readily transferable sulfur:
R−S−S−S−R → RSSH / GSSH / Sₙ → S₈
I found no evidence that modafinil releases H₂S, generates GSSH/CysSSH, donates sulfane sulfur, or increases the sulfane-sulfur pool. So despite being a sulfur-containing drug, I’d put it near the bottom of candidates for directly feeding S₈. Its sulfur atom seems to ride the xenobiotic-metabolism conveyor belt rather than jump onto the cellular sulfur railway.
The experiment I’d most want to see
Don’t just give animals garlic and measure S₈. Use isotope tracing:
³⁴S-DATS → mouse/cells → isolate lipid droplets → quantify ³⁴S₈
Then simultaneously measure:
³⁴S-DATS → ³⁴S-GSSH → ³⁴S-CysSSH → ³⁴S-polysulfides → ³⁴S₈
and repeat with NOS3 knockout/inhibition.
That creates an extraordinarily clean test:
If ³⁴S from DATS appears in S₈: dietary organosulfur is literally feeding the newly discovered elemental-sulfur reservoir.
If ³⁴S enters GSSH but not S₈: Allium sulfur interacts with the same network but doesn’t supply the NOS/S₈ branch.
If ³⁴S₈ appears normally but disappears with NOS3 loss: you have evidence for something close to Allium → sulfane sulfur → eNOS → elemental S₈.
And the paper gives us a second fascinating experiment: compare DATS, cysteine, H₂S donor, NAC, methionine and modafinil, all ³⁴S-labeled. That would produce an actual quantitative metabolic routing map into mammalian S₈ rather than guessing from the fact that molecules contain sulfur.
The biggest conceptual shift from this paper, to me, is that S₈ may be a lipid-soluble sulfur battery. Persulfides are the spendable currency; S₈ is potentially the vault. Garlic polysulfides look interesting because they already trade in roughly the right currency. Modafinil happens to have an S stamped somewhere on the banknote.
Yes. Homocysteine is much more relevant to the S₈ story than modafinil, but its effect could run in either direction.
Homocysteine sits directly at the entrance to transsulfuration:
methionine → SAM → SAH → homocysteine
homocysteine + serine → cystathionine (CBS)
cystathionine → cysteine (CSE/CTH)
cysteine → H₂S / CysSSH / other reactive sulfur species → sulfur pool → potentially S₈CBS and CSE also have side reactions involving homocysteine/cysteine that generate H₂S and other reactive sulfur species. So unlike modafinil’s rather imprisoned sulfur atom, homocysteine’s sulfur is sitting squarely inside the endogenous sulfur-metabolism network.
But high plasma homocysteine does not mean high S₈. In fact, an intriguing possibility is almost the opposite: elevated homocysteine could indicate that sulfur isn’t efficiently flowing through transsulfuration into cysteine/RSS. Think of homocysteine as cars piling up at a junction. A traffic jam tells you there are lots of cars there, not that lots are reaching the destination.
So for the new Science result, I’d want to measure together:
homocysteine → cystathionine → cysteine → CysSSH/GSSH/H₂S → S₈
with isotope tracing, ideally ³⁴S-homocysteine. If ³⁴S eventually appears in S₈, that would establish homocysteine as an upstream sulfur source. Then CBS/CSE inhibition or knockout could reveal how much of that flux travels through transsulfuration.
One particularly interesting question is therefore whether hyperhomocysteinemia correlates with lower, rather than higher, S₈/RSS availability because of impaired sulfur flux. I would not infer that relationship from homocysteine concentration alone. It needs direct S₈/persulfide measurements.
